Biarylmethyl heterocycles

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein all variables are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are biased agonists, or β-Arrestin agonists of the angiotensin II receptor, which may be used as medicaments.

FIELD OF THE INVENTION

The present invention provides substituted biaryl compounds and theiranalogues thereof, acting as biased agonists at the Angiotensin IIreceptor, compositions containing them, and methods of using them, forexample, for the treatment or prophylaxis of cardiovascular diseases,such as chronic heart failure or chronic hypertensive conditions.

BACKGROUND OF THE INVENTION

Cardiovascular disease and mortality continue to represent the leadingcause of death in developed countries despite significant advances inunderstanding of disease progression and the availability of newtreatments. Within this context, heart failure continues to be a growinghealthcare problem with millions of new cases occurring worldwideannually. Morbidity and mortality of those patients presenting inhospital for decompensation is high with approximately 35% of thesepatients dying or requiring re-hospitalization within 3 months ofdischarge (Bhatia, Tu et al. 2006, Fonarow, Stough et al. 2007,Gheorghiade, Vaduganathan et al. 2013); 50% of heart failure patientsdie within 5 years of diagnosis (Go, Mozaffarian et al. 2013,Mozaffarian, Benjamin et al. 2015). As a result, heart failurerepresents a significant burden to human health and the efficientadministration of healthcare services (Desai and Stevenson 2012, Go,Mozaffarian et al. 2013, Mozaffarian, Benjamin et al. 2015).

There are currently two forms of heart failure recognized and classifiedbased upon their etiology and pathogenesis (Satomura, Wada et al.).Heart failure with reduced ejection fraction (HFrEF, systolic heartfailure) typically follows ischemic insult such as myocardialinfarction, coronary artery disease or underlying cardiomyopathies andis characterized by significant cardiac scarring, fibrosis, thinning ofthe left ventricular wall, left ventricular dilation and a concomitantreduction in left ventricular ejection fraction. Heart failure withpreserved ejection fraction (HFpEF, diastolic heart failure) isgenerally a result of chronic increased cardiac load associated withchronic hypertension resulting in cardiac remodeling, thickening of theleft ventricular wall, fibrosis and reduced left ventricular volume. Inthe early stages of HFpEF, tissue remodeling and thickening of theventricular wall can compensate for the increased load and maintainejection fraction. However, as the disease progresses continuedmaladaptive remodeling leads to failure of ventricular function. Theimpact of heart failure on the health of the patient can be assessed bythe myriad of symptoms associated with the disease including dyspnea,exercise intolerance, pulmonary and peripheral edema and chronicfatigue. Current effective therapies exist for HFrEF but not HFpEF.

Among the clinically accepted standard of care for HFrEF are diureticsthat reduce volume overload and dyspnea associated with reducedperfusion, as well as angiotensin-converting enzyme (ACE) inhibitors(ACEi) and angiotensin receptor blockers (ARBs) (Yancy, Jessup et al.2013). Drugs such as ACEi and ARBs target the renin-angiotensinaldosterone system (RAAS). The RAAS system is a physiologicallyimportant endocrine/paracrine pathway through its actions to maintainhomeostatic blood pressure and cardiac output. The RAAS pathway isgenerally activated during conditions such as renal dysfunction andheart failure due to reduced kidney function that induces release ofrenin by the kidneys. Renin is a circulating enzyme that convertsangiotensinogen to angiotensin I. In turn, angiotensin I is converted tothe vasoactive hormone angiotensin II (AII) by angiotensin-convertingenzyme (ACE) in the lung and other tissues. AII exerts its effects ontarget tissues through binding to specific receptors on these cells, theAT1R and AT2R receptors.

AT1R is thought to be the predominant AII receptor based upon expressionlevel. The AT1R works primarily through activation of the Gq signalingpathway within cells. However, AT1R has also been shown to activateother signaling pathways including non-G-protein-mediated pathways suchas β-arrestin (Wei, Ahn et al. 2003, Aplin, Christensen et al. 2007).

Therapeutically, ACEi block AII production through inhibition of theconversion of angiotensin I to AII (Brown and Vaughan 1998), while ARBsspecifically block AII action via competitive antagonism of the AIIreceptor, AT1R (Gring and Francis 2004). The resultant blockade of AIIactivity results in lowering of blood pressure and cardiac load. ARBshave the added benefit of improving kidney function through maintenanceof glomerular filtration and therefore improved diuresis andnatriuresis. Recently, combination therapy containing an ARB+neprilysininhibitor has shown improved benefit in tolerant HFrEF patients over ARBalone (McMurray, Packer et al. 2014). Furthermore, AT1R biased agonistpeptides have also shown the ability to improve renal function inpreclinical models of heart failure (Boerrigter, Soergel et al. 2012)and in humans (Soergel, Subach et al. 2013, Felker, Butler et al. 2015).

Despite their differences in mechanism, ACEi and ARBs continue to bemainstays of therapeutic intervention in heart failure patients (Yancy,Jessup et al. 2013). However, it is now appreciated that, in addition tothe detrimental effects of AII action on the cardio-renal system, AIIcan also have some beneficial effects through activation of non-Gqsignaling pathways, most notably β-arrestin. Indeed, peptidergic analogsof AII (e.g. SII) have been found to be biased agonists of AT1R. Forexample, the SII peptide has been found to bind AT1R and activateβ-arrestin signaling but not Gq signaling (Rajagopal, Whalen et al.2006, Kendall, Strungs et al. 2011). This peptide has been shown tostimulate cardiomyocyte contractility and prevent apoptosis (Rajagopal,Whalen et al. 2006). Biased agonist peptides to AT1R, have also beenshown to lower blood pressure and improve cardiac function in animalmodels of heart failure (Violin, DeWire et al. 2010, Kim, Abraham et al.2012) and in human clinical trials (Soergel, Subach et al. 2013, Felker,Butler et al. 2015).

In addition to being recognized as key treatments for HFrEF, blockade ofAT1R signaling has been used extensively in the clinic to treathypertension. Hypertension is a recognized risk factor for microvascularand macrovascular diseases and there is significant literaturesupporting the beneficial effects of reducing blood pressure inimproving these risks (Staessen, Li et al. 2005, Farsang 2011). AIIblockade is a first line therapy for the treatment of clinicalhypertension (James, Oparil et al. 2014) and has been shown to decreasethe relative risk for both heart failure (Ong, Ong et al. 2013) andstroke (Ravenni, Jabre et al. 2011) in susceptible patients.Furthermore, chronic hypertension is a key determinant for HFpEF(Kitzman, Little et al. 2002, Owan and Redfield 2005). In addition toincreasing blood pressure via activation of Gq signaling pathways insmooth muscle cells, AII also is a pro-inflammatory stimulus for thevascular endothelium through its regulation of key anti-inflammatorygenes (Luft 2002, Dandona, Dhindsa et al. 2006). ARBs have been shown toinhibit the pro-inflammatory effects of AII in endothelial cells atleast partially through blocking Gq-dependent negative regulation ofendothelial nitric oxide synthase (eNOS) (Main 2005, Mason, Jacob et al.2012). Interestingly, the impact of AT1R activation to affectendothelial function does not require AII but can also be impacted bymechanical forces imposed on the cell (Mederos y Schnitzler, Storch etal. 2011, Tang, Strachan et al. 2014). In one instance, the impact ofmechanical force on AT1R has been shown to allosterically promoteβ-arrestin signaling by an AT1R biased agonist (Tang, Strachan et al.2014). Activation of AT1R by mechanical stretch has also been noted incardiomyocytes (Mederos y Schnitzler, Storch et al. 2011).

These data suggest that biased agonism (preferential activation of somesignaling pathways (including β-arrestin) over the Gq signaling pathway)of the AT1R could have long term benefit in heart failure patients byaltering AII signaling via AT1R in several cell types. Biasing of AT1Rsignaling could prove a significant improvement on ARBs that block allthe signaling outputs of the AT1R. Unfortunately, peptide-basedtherapies have limitations in dosing that restrict their ability to beused as a chronic therapy and in less advanced heart failure. Therefore,development of safe and efficacious synthetic biased agonists ormodulators of AT1R could significantly improve treatment of HFrEF andHFpEF patients through not only unloading the heart but also throughactivation of beneficial signaling pathways directly in cardiomyocytes.Similarly, anti-fibrotic activities combined with antihypertensiveeffects associated with AT1R biased agonism further suggests potentialfor this mechanism in treatment of HFpEF.

Recently, a series of peptidic compounds have been disclosed inWO10077339 demonstrating the possible therapeutic effects ofpreferentially agonizing β-Arrestin recruitment while minimizing Gqsignaling at the AT1 receptor. These peptides have exhibited thepotential for cardiovascular benefits in an acute clinical settingfollowing intravenous administration (Soergel, Subach et al. 2013,Felker, Butler et al. 2015, Pang, Butler et al. 2017). However, study ofan AT1R biased agonist peptide in acute decompensated heart failurepatients using a 48-96 h infusion did not meet its composite primary endpoint (Pang, Butler et al. 2017). Interestingly, acute treatment ofstable, chronic heart failure patients with an infusion of this biasedagonist peptide did show significant improvement in left ventricularfilling pressure and arterial pressure, especially those with elevatedRAAS (Soergel, R. A. Subach et al. 2013). Furthermore, preclinical datain mouse models of heart failure using this peptide or close analogshave found that they have direct cardiac effects to improve cardiacfunction not seen with ARBs (Abraham, Davis et al. 2016). Takentogether, these data suggest it is possible that this mechanism does notlend itself to acute/sub-acute treatment but perhaps is better suited asa chronic therapy alone or in combination with other heart failuremedicines, such as ACEi. In light of this potential, the discovery of anorally bioavailable biased modulator of the AT1 receptor remains animportant research goal.

In this application we describe the invention of a series ofnon-peptide, β-arrestin biased modulators of the AT1 receptor intendedfor the chronic treatment of cardiovascular disease. Though non-peptideagonists of the AT1 receptor have been previously described in U.S. Pat.No. 5,444,067 and in several academic publications (Perlman, Schambye etal. 1995, Perlman, Costa-Neto et al. 1997, Miura, Kiya et al. 2012), theagonist activity observed in these documents was correlated to anincreased stimulus in phosphoinositide hydrolysis, which is a knownbiomarker for increased Gq signaling. Thus, when a representativeagonist from these works was examined in vivo it was found to causeincreased vascular resistance in a manner analogous to the native AIIligand (De Witt, Garrison et al. 2000). The desire for, oridentification of, a non-peptide biased agonist preferentially agonizingthe β-arrestin signaling pathway via AT1R is not contemplated in any ofthese documents. The present invention describes the identification ofnon-peptide small molecule AT1R biased agonists that selectively agonizeβ-arresting signaling in preference to Gq signaling.

SUMMARY OF THE INVENTION

The present invention provides substituted biaryl compounds, andanalogues thereof, which are useful as Angiotensin II biased agonists,or β-Arrestin agonists of the Angiotensin II Receptor, includingstereoisomers, tautomers, pharmaceutically acceptable salts, or solvatesthereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of diseases or disorder associated with biased agonism ofthe Angiotensin II Receptor (defined as preferential activation of someAT1R-dependent signaling pathways (including β-arrestin) overAT1R-dependent Gq signaling), such as heart failure with preservedejection fraction (HFpEF), heart failure with reduced ejection fraction(HFrEF), and renal disease.

In addition to the effects as biased agonists of AT1R, as selectiveligands to the AT1R, the compounds of the invention may be used in thetreatment and/or prophylaxis of multiple diseases or disordersassociated with the AT1R, such as heart failure, coronary arterydisease, cardiomyopathy, fibrosis, atrial fibrillation, diabetes andrelated conditions including but not limited to acute coronary syndrome,myocardial ischemia, hypertension, atherosclerosis, pulmonaryhypertension, peripheral arterial disease, coronary vasospasm, cerebralvasospasm, ischemia/reperfusion injury, angina, renal disease, obesity,metabolic syndrome and insulin resistance.

The compounds of the invention may be used in the treatment and/orprophylaxis of multiple diseases or disorders associated withAT1R-mediated recruitment of β-arrestin and/or other non-Gq mediatedsignaling, such as HFpEF, HFrEF, and renal disease.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment and/or prophylaxis of multiple diseases ordisorders associated with AT1R-mediated recruitment of β-arrestin and/orother non-Gq mediated signaling.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present disclosure provides, inter alia, acompound of Formula (X):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, wherein:

ring A is

-   W is N, or CR¹⁶;-   W′, at each occurrence, is independently selected from N, O, S and    CR¹⁶, wherein at least one W′ is not CR¹⁶, and at most only one W′    is selected as O or S;-   R¹ and R² are independently selected from H, C₁-C₆ alkyl, C₁-C₆    haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxyalkyl, and C₃-C₆    cycloalkyl;-   alternatively, R¹ and R², together with the atom to which they are    attached, join together to form a C₃-C₆ cycloalkyl, or a 4 to 6    membered heterocycle having 1-2 heteroatoms, the cycloalkyl or    heterocycle is substituted with 0-4 F and 0-1 OH;-   R¹⁶, at each occurrence, is independently selected from H, F, Cl,    Br, I, CN, OH, N(R^(a))₂, C₁-C₃-alkyl, C₁-C₃-haloalkyl,    C₁-C₃-alkoxy, C₁-C₄-hydroxyalkyl, C₁-C₃-haloalkoxy,    C₃-C₆-cycloalkyl, and C₃-C₆-halocycloalkyl-   R^(a) is, at each occurrence, independently selected from H, C₁-C₄    alkyl, C₁-C₄-haloalkyl, C₁-C₄-hydroxyalkyl, and C₃-C₆-cycloalkyl;-   or two R^(a), along with the nitrogen atom to which they are    attached, join to form a 5 to 6 membered heterocycle containing 0-2    additional heteroatoms selected from N, O and S;-   Y is 5-tetrazolyl, SO₃H, PO₂H, PO₃H₂, COOR,

-   R, at each occurrence, is independently selected from H, C₁-C₆    alkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl,    C₆₋₁₀-aryl-C₁-C₆ alkyl, heterocycle-C₁-C₆ alkyl, wherein said    heterocycle is a 4-10 membered group having 1-3 heteroatoms selected    from N, O, or S, said aryl and heterocycle are each substituted with    0-3 groups chosen from C₁-C₃ alkyl, halo, OH, or C₁-C₃ fluoroalkyl;-   R^(s) at each occurrence, is independently selected from H, C₁-C₆    alkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇    cycloalkyl C₁-C₃ alkyl, C₆₋₁₀ aryl, C₆₋₁₀ aryl C₁-C₆ alkyl,    heteroaryl, heteroaryl-C₁-C₆-alkyl, heterocyclyl,    heterocycle-C₁-C₆-alkyl, wherein the heteroaryl is a 5-10 membered    group and the heterocycle is a 4-10 membered each having 1-3    heteroatoms selected from N, O, or S;-   Z, at each occurrence, is independently selected from a bond, O, S,    N(R^(z)), C(R^(z))₂, C═O, C(═O)N(R^(z)), N(R^(z))C(═O),    C(R^(z))₂C(R^(z))₂, OC(R^(z))₂, SC(R^(z))₂, N(R^(z))C(R^(z))₂,    C(R^(z))₂O, C(R^(z))₂S, C(R^(z))₂N(R^(z));-   R^(z) is at each occurrence independently selected from H,    C₁-C₄-alkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxyalkyl, C₁-C₄-haloalkyl,    C₃-C₁₀-cycloalkyl, 5-10-membered heterocycle-C₁-C₆-alkyl,    5-10-membered heterocycle, C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl, 4 to 7    membered heterocyclyl having 1-2 heteroatoms selected from N, O, or    S, or, alternatively, two R^(z) groups either on the same atom or on    adjacent atoms can join to form a C₃-C₆-cycloalkyl or a 4 to 7    membered heterocycle containing 1-2 heteroatoms selected from N, O    and S;-   G is selected from a 4 to 11 membered heterocycle having 1-4 atoms    selected from N, O, and S, a C₃-C₈-cycloalkyl, C₆-C₁₀-aryl or a 5 to    10 membered heteroaryl having 1-4 atoms selected from N, O, and S;    wherein the heterocycle, cycloalkyl, aryl and heteroaryl are    substituted with 0-3 substituents independently selected from the    group consisting of ═O, F, Cl, Br, I, C₁-C₆-alkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₈ cycloalkyl, C₃-C₈    cycloalkenyl, CH₂-phenyl, OH, OR^(x), SR^(x), N(R^(x))₂, CO(R^(x)),    CON(R^(x))₂, CO₂R^(x), N(R^(x))CO₂(R^(x)), N(R^(x))CO(R^(x)),    N(R^(x))CON(R^(x))₂, S(O)₂(R^(x)), S(O)₂N(R^(x))₂, or    N(R^(x))S(O)₂(R^(x)); R^(x) is H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄    hydroxyalkyl, phenyl, CH₂-phenyl;-   ring B is

-   Group C is

-   R³ is C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₁₋₆-hydroxycycloalkyl,    C₁₋₆-halocycloalkyl, COOR, CON(R^(z))₂, 5-6 membered heteroaryl of

-   R⁴ is H, F, Cl, Br, CF₃, CN, N(R^(z))₂, CON(R^(z))₂, C₁₋₄ alkyl,    C₁₋₄ haloalkyl C₁₋₄ alkoxyalkyl, C₁₋₄ hydroxyalkyl, C₃₋₆-cycloalkyl,    C₃₋₆-halocycloalkyl, C₃₋₆-alkoxycycloalkyl,    C₃-C₆-cycloalkyl-C₁-C₆-alkyl, or C₃₋₆-hydroxycycloalkyl;-   R⁵ is C₁₋₆ alkyl, C₁₋₆ haloalkyl; C₁₋₆ alkoxyalkyl,    C₃₋₆-cycloalkyl-C₀₋₄-alkyl which may be substituted with 1-3    halogens or a C₁₋₃-alkoxy group;-   R⁶ is H, F, Cl, Br, CF₃, CN, N(R^(z))₂, CON(R^(z))₂, C₁₋₄-alkyl,    C₁₋₄-haloalkyl, C₁₋₄-alkoxyalkyl, C₁₋₄ hydroxyalkyl,    C₃₋₆-cycloalkyl, C₃₋₆-halocycloalkyl, C₁₋₆alkoxy-C₃-C₆-cycloalkyl,    or C₃₋₆-hydroxycycloalkyl; and-   R⁷ and R⁸, are independently selected from H, C₁-C₄-alkyl,    C₁-C₄-hydroxyalkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl or,    alternatively, R⁷ and R⁸, along with the atom to which they are    attached, can join to form a C₃-C₉ cycloalkyl, a    C₃-C₉-halocycloalkyl, a C₃-C₉-hydroxycycloalkyl or a 4 to 7 membered    heterocycle having 1-2 heteroatoms selected from N, O, or S each of    said cycloalkyl and heterocycle being optionally substituted with    1-4 F, OH, C₁₋₄ alkyl, C₁₋₄ haloalkyl C₁₋₄ alkoxyalkyl, or C₁₋₄    hydroxyalkyl, and may be fused with a 6-membered aryl or 5-6    membered heteroaryl ring,-   provided the compounds of Formula (X) are not

In another aspect, the present disclosure provides, inter alia, acompound of Formula (I):

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, wherein:

-   ring A is

-   W is N, or CR¹⁶;-   W′, at each occurrence, is independently selected from N, O, S and    CR¹⁶, wherein at least one W′ is not CR¹⁶, and at most only one W′    is selected as O or S;-   R¹ and R² are independently selected from H, C₁-C₆ alkyl, C₁-C₆    haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxyalkyl, and C₃-C₆    cycloalkyl;-   alternatively, R¹ and R², together with the atom to which they are    attached, join together to form a C₃-C₆ cycloalkyl, or a 4 to 6    membered heterocycle having 1-2 heteroatoms, the cycloalkyl or    heterocycle is substituted with 0-4 F and 0-1 OH;-   R¹⁶, at each occurrence, is independently selected from H, F, Cl,    Br, I, CN, OH, N(R^(a))₂, C₁-C₃-alkyl, C₁-C₃-haloalkyl,    C₁-C₃-alkoxy, C₁-C₄-hydroxyalkyl, C₁-C₃-haloalkoxy,    C₃-C₆-cycloalkyl, and C₃-C₆-halocycloalkyl-   R^(a) is, at each occurrence, independently selected from H,    C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-hydroxyalkyl, and    C₃-C₆-cycloalkyl;-   or two R^(a), along with the nitrogen atom to which they are    attached, join to form a 5 to 6 membered heterocycle containing 0-2    additional heteroatoms selected from N, O and S;-   Y is 5-tetrazolyl, SO₃H, PO₂H, PO₃H₂, COOR,

-   R, at each occurrence, is independently selected from H, C₁-C₆    alkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl,    C₆₋₁₀-aryl-C₁-C₆ alkyl, heterocycle-C₁-C₆ alkyl, wherein said    heterocycle is a 4-10 membered group having 1-3 heteroatoms selected    from N, O, or S, said aryl and heterocycle are each substituted with    0-3 groups chosen from C₁-C₃ alkyl, halo, OH, or C₁-C₃ fluoroalkyl;-   R^(s) at each occurrence, is independently selected from H, C₁-C₆    alkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇    cycloalkyl C₁-C₃ alkyl, C₆₋₁₀ aryl,-   C₆₋₁₀ aryl C₁-C₆ alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,    heterocyclyl, heterocycle-C₁-C₆-alkyl, wherein the heteroaryl is a    5-10 membered group and the heterocycle is a 4-10 membered each    having 1-3 heteroatoms selected from N, O, or S;-   Z, at each occurrence, is independently selected from a bond, O, S,    N(R^(z)), C(R^(z))₂, C═O, C(═O)N(R^(z)), N(R^(z))C(═O),    C(R^(z))₂C(R^(z))₂, OC(R^(z))₂, SC(R^(z))₂, N(R^(z))C(R^(z))₂,    C(R^(z))₂O, C(R^(z))₂S, C(R^(z))₂N(R^(z));-   R^(z) is at each occurrence independently selected from H,    C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl    or, alternatively, two R^(z) groups either on the same atom or on    adjacent atoms can join to form a C₃-C₆-cycloalkyl or a 4 to 7    membered heterocycle containing 1-2 heteroatoms selected from N, O    and S;-   G is selected from a 4 to 11 membered heterocycle having 1-4 atoms    selected from N, O, and S, a C₃-C₈-cycloalkyl, C₆-C₁₀-aryl or a 5 to    10 membered heteroaryl having 1-4 atoms selected from N, O, and S;    wherein the heterocycle, cycloalkyl, aryl and heteroaryl are    substituted with 0-3 substituents independently selected from the    group consisting of ═O, F, Cl, Br, I, C₁-C₆-alkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, OH, OR^(x), SR^(x), N(R^(x))₂,    CO(R^(x)), CON(R^(x))₂, CO₂R^(x), N(R^(x))CO₂(R^(x)),    N(R^(x))CO(R^(x)), N(R^(x))CON(R^(x))₂, S(O)₂(R^(x)),    S(O)₂N(R^(x))₂, or N(R^(x))S(O)₂(R^(x));-   R^(x) is H, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₁₋₄ hydroxyalkyl, phenyl,    CH₂-phenyl;-   ring B is

-   Group C is

-   R³ is C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₁₋₆-hydroxycycloalkyl,    C₁₋₆-halocycloalkyl, COOR, CON(R^(z))₂, or

-   R⁴ is H, F, Cl, Br, CF₃, CN, N(R^(z))₂, CON(R^(z))₂, C₁₋₄ alkyl,    C₁₋₄ haloalkyl C₁₋₄ alkoxyalkyl, C₁₋₄ hydroxyalkyl, C₁₋₆-cycloalkyl,    C₁₋₆-halocycloalkyl, C₁₋₆-alkoxycycloalkyl, or    C₁₋₆-hydroxycycloalkyl;-   R⁵ is C₁₋₆ alkyl, C₁₋₆ haloalkyl; C₁₋₆ alkoxyalkyl,    C₁₋₆-cycloalkyl-C₀₋₄-alkyl which may be substituted with 1-3    halogens or a C₁₋₃-alkoxy group;-   R⁶ is H, F, Cl, Br, CF₃, CN, N(R^(z))₂, CON(R^(z))₂, C₁₋₄-alkyl,    C₁₋₄-haloalkyl, C₁₋₄-alkoxyalkyl, C₁₋₄ hydroxyalkyl,    C₁₋₆-cycloalkyl, C₁₋₆-halocycloalkyl, C₁₋₆alkoxycycloalkyl, or    C₁₋₆-hydroxycycloalkyl; and-   R⁷ and R⁸, are independently selected from H, C₁-C₄-alkyl,    C₁-C₄-hydroxyalkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl or,    alternatively, R⁷ and R⁸, along with the atom to which they are    attached, can join to form a C₃-C₆-cycloalkyl, a    C₃-C₆-halocycloalkyl, a C₃-C₆-hydroxycycloalkyl or a 4 to 7 membered    heterocycle having 1-2 heteroatoms selected from N, O, or S and the    potential for further substitution with 1-4 F, OH, C₁₋₄-alkyl,    C₁₋₄-haloalkyl C₁₋₄-alkoxyalkyl, C₁₋₄-hydroxyalkyl,-   provided the compounds of Formula (I) are not

In the various aspects described hereinafter below, the variousembodiments are equally applicable to Formula (I) or Formula (X), evenif they state only one of Formula (I) and Formula (X).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Group C is

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R¹ and R² are H;-   R³ is H, C₁₋₂ hydroxyalkyl, CO₂H, CO₂—C₁₋₆-alkyl, CONH₂,    CONH(C₁₋₆-alkyl), CON(C₁₋₆-alkyl)₂, or

-   R⁴ is H, F, Cl, Br, CF₃, CN, C₁₋₃ alkyl, C₁₋₃ haloalkyl, or C₁₋₂    hydroxyalkyl;--   R⁵ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or O(C₁₋₆ alkyl);-   R⁶ is hydrogen, or C₁₋₄ alkyl;-   R⁷ and R⁸ are H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, or C₁₋₃ hydroxyalkyl-   alternatively, R⁷ and R⁸, along with the atom to which they are    attached, join to form a C₃-C₆-cycloalkyl or a C₄-C₇-heterocycle;    and-   R is H, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, or

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Group C is

-   R¹ and R² are H;-   R³ is hydroxyalkyl, CO₂H, or

-   R⁴ is C₁₋₃ alkyl, C₁₋₃ haloalkyl, or C₁₋₃ hydroxyalkyl; and-   R⁵ is ethyl, n-propyl, or n-butyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   G is selected from a 5 to 10 membered heterocycle having 1-3 atoms    selected from N, O, and S, phenyl or a C₆-C₁₀-heteroaryl having 1-3    atoms selected from N, O, and S; wherein the heterocycle, phenyl and    heteroaryl are substituted with 0-3 substituents independently    selected from the group consisting of ═O, Cl, Br, I, F, C₁-C₆-alkyl,    C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-alkylthio, C₁-C₆-hydroxyalkyl,    OH, OR^(x), N(R^(x))₂, CO(R^(x)), CON(R^(x))₂, CO₂R^(x),    N(R^(x))CO₂(R^(x)), N(R^(x))CO(R^(x)), N(R^(x))CON(R^(x))₂,    S(O)₂(R^(x)), S(O)₂R^(x), S(O)₂N(R^(x))₂, N(R^(x))S(O)₂(R^(x)), or    N(R^(x))S(O)₂R^(x);-   R^(x) is H, C₁₋₆ alkyl, CF₃, phenyl, CH₂-phenyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring B is

any of which are optionally substituted with 0-2 F,

Y is COOH, COOMe, COOEt,

5-tetrazolyl, SO₃H,

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   wherein Y is COOH, 5-tetrazolyl, SO₃H,

and

-   R^(s) is C₁₋₆ alkyl, C₆₋₁₀-aryl-C₁-C₆-alkyl, or (CH₂Ph).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring A is

and

R^(a) is H or F.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   G is selected from a phenyl, thiophenyl, quinolinyl, isoquinolinyl,    indolyl, pyrazolyl, pyrrolyl, pyridinyl, isoindolinyl, pyrrolidinyl;    any of which are substituted with 0-3 substituents independently    selected from the group consisting of ═O, Cl, Br, I, F, C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, OH, OR^(x), N(R^(x))₂,    CO(R^(x)), CON(R^(x))₂, CO₂R^(x), N(R^(x))CO₂(R^(x)),    N(R^(x))CO(R^(x)), N(R^(x))CON(R^(x))₂, S(O)₂(R^(x)),    S(O)₂N(R^(x))₂, or N(R^(x))S(O)₂R^(x); and-   R^(x) is H, C₁₋₃ alkyl, CF₃, phenyl, CH₂-phenyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Y is COOH, 5-tetrazolyl,

andR^(s) is C₁₋₆ alkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring B is

any of which are substituted with 0-2 F.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring B is

any of which are substituted with 0-2 F;

Ring A is

-   Z is a bond or NR^(a);-   G is isoindolinyl-1,3-dione, pyrrolidine-2,5-dione, phenyl,    thiazolyl, pyridinyl, pyrrolyl, pyrazolyl, quinolinyl,    isoquinolinyl, any of which may be substituted with 0-3 substituents    selected from ═O, C₁₋₄ alkyl, —O—R^(x), C₁₋₄ haloalkyl, —C(O)NR^(x),    —N(R^(x))₂, and F;-   R⁵ is C₃₋₄ alkyl;-   R⁶ is C₃₋₄ alkyl;-   R^(a) is hydrogen, C₁₋₄-alkyl, and C₁₋₂-haloalkyl; and-   Y is tetrazolyl, COOH, 1,2,4-oxadiazol-5(4H)-one, or    —SO₂NHCOO-nbutyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   ring A is

-   W is N, or CR¹⁶;-   W′, at each occurrence, is independently selected from N, O, S and    CR¹⁶ where at least one W′ is not CR¹⁶, and at most only one W′ is    selected as O or S;-   R¹ and R² are independently selected from H, C₁-C₆ alkyl, C₁-C₆    haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxyalkyl, and C₃-C₆    cycloalkyl;-   alternatively, R¹ and R², together with the atom to which they are    attached, join together to form a C₃-C₆ cycloalkyl, or a 4- to    6-membered heterocycle having 1-2 heteroatoms, the cycloalkyl or    heterocycle is substituted with 0-4 F and 0-1 OH;-   R¹⁶, at each occurrence, is independently selected from H, F, Cl,    Br, I, CN, OH, N(R^(a))₂, C₁-C₃-alkyl, C₁-C₃-haloalkyl,    C₁-C₃-alkoxy, C₁-C₄-hydroxyalkyl, C₁-C₃-haloalkoxy,    C₃-C₆-cycloalkyl, and C₃-C₆-halocycloalkyl;-   R^(a) is, at each occurrence, independently selected from H,    C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-hydroxyalkyl, and    C₃-C₆-cycloalkyl;-   or two R^(a), along with the nitrogen atom to which they are    attached, join to form a 5 to 6 membered heterocycle containing 0-2    additional heteroatoms selected from N, O and S;-   Y is 5-tetrazolyl, SO₃H, PO₂H, PO₃H₂, COOR,

-   R, at each occurrence, is independently selected from H, C₁-C₆    alkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl,    C₆₋₁₀-aryl-C₁-C₆ alkyl, heterocycle-C₁-C₆ alkyl, wherein said    heterocycle is a 4-10 membered group having 1-3 heteroatoms selected    from N, O, or S, said aryl and heterocycle are each substituted with    0-3 groups chosen from C₁-C₃ alkyl, halo, OH, or C₁-C₃ fluoroalkyl;-   R^(s) at each occurrence, is independently selected from H, C₁-C₆    alkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇    cycloalkyl-C₁-C₃ alkyl, C₆₋₁₀ aryl, C₆₋₁₀-aryl-C₁-C₆ alkyl,    heteroaryl, heteroaryl-C₁-C₆-alkyl, heterocyclyl,    heterocycle-C₁-C₆-alkyl, wherein the heteroaryl and heterocycle are    each a 4-10 membered group having 1-3 heteroatoms selected from N,    O, or S;-   Z, at each occurrence, is independently selected from a bond, O, S,    N(R^(z)), C(R^(z))₂, C═O, C(═O)N(R^(z)), N(R^(z))C(═O),    C(R^(z))₂C(R^(z))₂, OC(R^(z))₂, SC(R^(z))₂, N(R^(z))C(R^(z))₂,    C(R^(z))₂O, C(R^(z))₂S, C(R^(z))₂N(R^(z));-   R^(z) is at each occurrence independently selected from H,    C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl    or, alternatively, two R^(z) groups either on the same atom or on    adjacent atoms can join to form a C₃-C₆-cycloalkyl or a 4 to 7    membered heterocycle containing 1-2 heteroatoms selected from N, O    and S;-   G is selected from a 4 to 11 membered heterocycle having 1-4 atoms    selected from N, O, and S, a C₃-C₈-cycloalkyl, C₆-C₁₀-aryl or a 5 to    10 membered heteroaryl having 1-4 atoms selected from N, O, and S;    wherein the heterocycle, cycloalkyl, aryl and heteroaryl are    substituted with 0-3 substituents independently selected from the    group consisting of ═O, F, Cl, Br, I, C₁-C₆-alkyl, C₁-C₆-alkoxy,    C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, OH, OR^(x), SR^(x), N(R^(x))₂,    CO(R^(x)), CON(R^(x))₂, CO₂R^(x), N(R^(x))CO₂(R^(x)),    N(R^(x))CO(R^(x)), N(R^(x))CON(R^(x))₂, S(O)₂(R^(x)),    S(O)₂N(R^(x))₂, or N(R^(x))S(O)₂(R^(x));-   R^(x) is H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, phenyl,    CH₂-phenyl;-   ring B is

-   Group C is

-   R⁵ is C₁₋₆ alkyl, C₁₋₆ haloalkyl C₁₋₆ alkoxyalkyl,    C₃₋₆-cycloalkylC₀₋₄-alkyl which may be substituted with 1-3 halogens    or a C₁₋₃-alkoxy group;-   R⁶ is H, F, Cl, Br, CF₃, CN, N(R^(z))₂, CON(R^(z))₂, C₁₋₄ alkyl,    C₁₋₄ haloalkyl C₁₋₄ alkoxyalkyl, C₁₋₄ hydroxyalkyl, C₃₋₆-cycloalkyl,    C₃₋₆-halocycloalkyl, C₁₋₆-alkoxy-C₃-C₆-cycloalkyl, or    C₁₋₆-hydroxycycloalkyl;-   R⁹ is COOR, CON(R^(z))₂; and-   r is 0 to 3;-   provided that the compounds of Formula (I) are not

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   R⁵ is C₁₋₆ alkyl, C₃₋₆ cycloalkyl or O(C₁₋₆ alkyl); and-   R⁶ is hydrogen, or C₁₋₄ alkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   G is selected from a 5 to 10 membered heterocycle having 1-3 atoms    selected from N, O, and S, phenyl or a C₆-C₁₀-heteroaryl having 1-3    atoms selected from N, O, and S; wherein the heterocycle, phenyl and    heteroaryl are substituted with 0-3 substituents independently    selected from the group consisting of ═O, Cl, Br, I, F, C₁-C₆-alkyl,    C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-alkylthio, C₁-C₆-hydroxyalkyl,    OH, OR^(x), N(R^(x))₂, CO(R^(x)), CON(R^(x))₂, CO₂R^(x),    N(R^(x))CO₂(R^(x)), N(R^(x))CO(R^(x)), N(R^(x))CON(R^(x))₂,    S(O)₂(R^(x)), S(O)₂N(R^(x))₂, or N(R^(x))S(O)₂R^(x);-   R^(x) is H, C₁₋₆ alkyl, CF₃, phenyl, CH₂-phenyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring B is

any of which are optionally substituted with 0-2 F,

In another aspect, there are disclosed compounds of Formula (IF) asdescribed by any of the other embodiments or aspects, including salts,enantiomers, diastereomers, tautomers, pharmaceutically-acceptablesalts, hydrates, or solvates thereof, wherein R⁹ is CO₂H, CO₂—C₁₋₆-alkyl, CO₂NH₂, CO₂NH(C₁₋₆-alkyl), CO₂N(C₁₋₆-alkyl)₂.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring B is

any of which are optionally substituted with 0-2 F,

Y is COOH, COOMe, COOEt,

5-tetrazolyl, SO₃H,

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

wherein Y is COOH, 5-tetrazolyl, SO₃H,

andR is C₁₋₆ alkyl, C₆₋₁₀-aryl-C₁-C₆-alkyl, or (CH₂Ph).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein: Ring A is

and

R^(a) is H or F.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   G is selected from a phenyl, thiophenyl, quinolinyl, isoquinolinyl,    indolyl, pyrazolyl, pyrrolyl, pyridinyl, isoindolinyl, pyrrolidinyl;    any of which are substituted with 0-3 substituents independently    selected from the group consisting of ═O, Cl, Br, I, F, C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, OH, OR^(x), N(R^(x))₂,    CO(R^(x)), CON(R^(x))₂, CO₂R^(x), N(R^(x))CO₂(R^(x)),    N(R^(x))CO(R^(x)), N(R^(x))CON(R^(x))₂, S(O)₂(R^(x)),    S(O)₂N(R^(x))₂, or N(R^(x))S(O)₂R^(x);-   R^(x) is H, C₁₋₃ alkyl, CF₃, phenyl, CH₂phenyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Y is carboxyl, 5-tetrazolyl,

andR is C₁₋₆ alkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring B is

any of which are substituted with 0-2 F.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring B is

Ring A is

Z is a bond or NR^(a);

-   G is isoindolinyl-1,3-dione, pyrrolidine-2,5-dione, phenyl,    thiazolyl, pyridinyl, pyrrolyl, pyrazolyl, quinolinyl,    isoquinolinyl, any of which may be substituted with 0-3 substituents    selected from ═O, C₁₋₄ alkyl, —O—R^(x), C₁₋₄ haloalkyl, —C(O)NR^(x),    —N(R^(x))₂, and F;-   R⁵ is C₃₋₄ alkyl;-   R⁶ is C₃₋₄ alkyl;-   R^(a) is hydrogen, C₁₋₄alkyl, and C₁₋₂haloalkyl; and-   Y is tetrazolyl, COOH, 1,2,4-oxadiazol-5(4H)-one, or    —SO₂NHCOO-nbutyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring A is

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring A is

R^(a) is H or F, or R^(a) is H.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Y is COOH, COOMe, COOEt,

5-tetrazolyl, SO₃H,

or Y is tetrazolyl, COOH, 1,2,4-oxadiazol-5(4H)-one, or—SO₂NHCOO-nbutyl;or Y is carboxyl, 5-tetrazolyl,

or Y is tetrazolyl, COOH, 1,2,4-oxadiazol-5(4H)-one, or—SO₂NHCOO-nbutyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Z is a bond or NR^(a), where R^(a) is hydrogen, C₁₋₄alkyl, or C₁₋₂    haloalkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   Z is a bond.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   G is selected from a phenyl, thiophenyl, quinolinyl, isoquinolinyl,    indolyl, pyrazolyl, pyrrolyl, pyridinyl, isoindolinyl, pyrrolidinyl;    any of which are substituted with 0-3 substituents independently    selected from the group consisting of ═O, Cl, Br, I, F, C₁-C₆-alkyl,    C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, OH, OR^(x), N(R^(x))₂,    CO(R^(x)), CON(R^(x))₂, CO₂R^(x), N(R^(x))CO₂(R^(x)),    N(R^(x))CO(R^(x)), N(R^(x))CON(R^(x))₂, S(O)₂(R^(x)), S(O)₂R^(x),    S(O)₂N(R^(x))₂, N(R^(x))S(O)₂(R^(x)), or N(R^(x))S(O)₂R^(x);-   or G is isoindolinyl-1,3-dione, pyrrolidine-2,5-dione, phenyl,    thiazolyl, pyridinyl, pyrrolyl, pyrazolyl, quinolinyl,    isoquinolinyl, any of which may be substituted with 0-3 substituents    selected from ═O, C₁₋₄ alkyl, —O—R^(x), C₁₋₄ haloalkyl, —C(O)NR^(x),    —N(R^(x))₂, and F.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

-   wherein Y is COOH, 5-tetrazolyl, SO₃H,

andR^(s) is C₁₋₆ alkyl, or (CH₂Ph).

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Ring B is

or Ring B is

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

Group C is

or Group C is

or Group C is

or Group C is

or Group C is

or Group C is

or Group C is of

or Group C is

or Group C is

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

R¹ and R² are H.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein:

R^(x) is H, C₁₋₆ alkyl, CH₂-phenyl; andR^(s) is C₁₋₆ alkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety:

is selected from the following:

whereR⁵ is C₁₋₄ alkyl, methoxymethyl, ethoxymethyl or cyclopropyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety:

is selected from the following:

where R⁴ is H, F, Cl, methyl or ethyl and R⁵ is C₁₋₄ alkyl,methoxymethyl, ethoxymethyl or cyclopropyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety:

is:

whereinR⁵ is C₁₋₄ alkyl, C₁₋₄ haloalkyl, or cyclopropylR⁷ and R⁸ are independently H, C₁₋₃ alkyl, or taken together join toform cyclopentyl, cyclohexyl, cycloheptyl, or tetrahydropyranyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety:

is selected from:

wherein R⁶ is independently H or Me; andR⁵ is C₁₋₂, alkyl, C₁₋₂, haloalkyl, methoxymethyl, or cyclopropyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety:

is selected from:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety:

is:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety

is selected from phenyl, pyridyl, pyrimidinyl or pyrazinyl, and ring

is phenyl or thiophenyl and R¹⁶ is as defined earlier.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety

is selected from the following:

where rings B and A can be substituted with 0-4 substituents chosenindependently from F, Cl, CN, methyl, ethyl, methoxy, or OCHF₂; and “C”indicates:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety

is selected from the following:

where rings B and A are substituted with 0-4 substituents selectedindependently from F, Cl, CN, methyl, ethyl, methoxy, or OCHF₂;and “C” indicates:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety Y is selected from the following:

wherein R^(a) is, at each occurrence, independently selected from H,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-hydroxyalkyl, and C₃-C₆-cycloalkyl;andR^(s) at each occurrence, is independently selected from H, C₁-C₆ alkyl,C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkylC₁-C₃ alkyl, C₆₋₁₀ aryl, C₆₋₁₀-aryl-C₁-C₆-alkyl, heteroaryl,heteroaryl-C₁-C₆-alkyl, heterocyclyl, heterocycle-C₁-C₆-alkyl, whereinthe heteroaryl is a 5-10 membered group and the heterocycle is a 4-10membered each having 1-3 heteroatoms selected from N, O, or S.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety Y is selected from the following:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein the moiety Y is selected from the following:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein Z is a bond and the moiety Z-G is selected from the following:phenyl, pyridyl, pyrazolyl, triazolyl, tetrahydropyranyl,tetrahydrofuranyl, morpholinyl, thiazolyl, isothiazolyl and imidazolyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein Z is a bond and the moiety Z-G is selected from the following:phenyl, pyrid-2-yl, pyrid-3-yl, pyrazol-1-yl, 1,2,3-triazol-4-yl,1,2,3-triazol-1-yl, indazol-1-yl, indazol-2-yl, benzotriazol-1-yl,tetrahydropyran-2-yl, tetrahydrofuran-2-yl, morpholin-2-yl,thiazol-2-yl, and isothiazol-3-yl, each said moiety being substitutedwith 0-3 substituents selected from F, Cl, OH, CN, C₁₋₃ alkyl, C₁₋₃alkoxy, C₁₋₃ fluoroalkyl, methoxyC₁₋₂alkyl, hydroxyC₁₂alkyl, and N(C₁₋₂alkyl)₂.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein Z is a bond and the moiety Z-G is selected from the following:

wherein

R″ is H, Cl, F, methyl, ethyl, cyclopropyl, methoxy, CHF₂, CF₃, CF₂CH₃,OCHF₂, N(CH₃)₂, or methoxymethyl;

R¹² is H, Cl, F, methyl, methoxy, hydroxymethyl, CHF₂, or CF₃;

R¹³ is H, F, Cl, CH₃, CHF₂, CF₃, or methoxy;

R¹⁴ is methyl, ethyl, i-propyl, cyclopropylmethyl, cyclobutylmethyl,n-butyl, butyl, CH₂CH₂F, CH₂CHF₂, or hydroxyethyl;

R¹⁵ is H, methyl, CF₃, CHF₂, hydroxymethyl, or hydroxyethyl;

R¹⁶ is H, methyl, CF₃, or CHF,

R¹⁷ is methyl, ethyl, propyl, cyclopropyl, i-propyl or t-butyl;

R¹⁸ is H, F, or OH;

R¹⁹ is H, F, Cl, methyl, or methoxy;

R²⁰ is H, or F; and

R²¹ is H, F, Cl, methyl, or methoxy.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of

Formula (I) as described by any of the other embodiments or aspects,including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein Z is a bond and the moiety Z-G is selected from the following:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein

Z is O, N, or C═O;

G is phenyl, pyridyl, or C₃₋₇ cycloalkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein Z is O, N, or C═O;

G is phenyl, pyrid-2-yl, pyrid-3-yl, cyclohexyl, cyclopentyl, each beingsubstituted with 0-2 substituents selected from F, Cl, OH, NH₂, C₁₋₃alkyl, C₁₋₃ alkoxy, and C₁₋₂fluoroalkyl.

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein Z-G is selected from the following:

In another aspect, there are disclosed compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, including salts, enantiomers, diastereomers, tautomers,pharmaceutically-acceptable salts, hydrates, or solvates thereof,wherein: the compound is selected from Examples 1-462.

In another aspect, there is disclosed a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and any one or morecompounds of Formula (I), or compounds of Formula (I) as described byany of the other embodiments or aspects, or a pharmaceuticallyacceptable salt thereof.

In another aspect, there is disclosed a method for the treatment orprophylaxis of one or more disease or disorder which can be modulated bybiased agonism of the angiotensin II receptor, comprising administeringto a patient in need of such treatment or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, wherein the disease or disorder is heart failure with preservedejection fraction, reduced ejection heart failure, and/or renal disease.

In another aspect, there is disclosed a method for the treatment orprophylaxis of one or more disease or disorder which can be modulated bybiased agonism of the angiotensin II receptor, wherein the compound ofany of the embodiments is administered in combination with at least oneother type of therapeutic agent.

In another aspect, there is disclosed a method for the treatment orprophylaxis of multiple diseases or disorders, comprising administeringto a patient in need of such treatment or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of Formula (I), orcompounds of Formula (I) as described by any of the other embodiments oraspects, wherein the disease or disorder is heart failure with preservedejection fraction, reduced ejection heart failure, and/or renal disease.

In another aspect, there is disclosed a method for the treatment orprophylaxis of diseases or disorders, wherein the compound of any of theembodiments is administered in combination with at least one other typeof therapeutic agent. In another aspect, the present invention providesa compound selected from the exemplified examples or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds within the scope of the tenth aspect.

In another embodiment, the compounds of the present invention have EC₅₀values ≤10 μM, in stimulating β-arrestin recruitment using the assaysdisclosed herein, preferably, EC₅₀ values 5 μM, more preferably, EC₅₀values ≤1 μM, even more preferably, EC₅₀ values 0.5 μM. Additionally,compounds of the present invention show efficacy in stimulatingβ-arrestin recruitment relative to AII of ≥30% Ymax, morepreferably >50% Ymax, and even more preferably >70% Ymax. Moreover,compounds of the present invention show activity in at least one of thethree β-arrestin assays disclosed herein. Preferred compounds of theinvention show activity in the BRET β-arrestin assay, and more preferredcompounds of the invention show activity in the BRET β-arrestin low AT1Rexpression assay. Additionally, the compounds may stimulate Gq activitywith efficacy (Ymax or Emax) less than 50% that of angiotensin II usingthe assays disclosed herein, preferably, Ymax≤30%, more preferablyYmax≤20%, even more preferably Ymax≤10%. In addition, preferredcompounds of the invention may show reduced potency (higher EC₅₀) in Gqsignaling assays relative to β-arrestin assays. These compounds may alsohave ability to activate other AT1R-dependent G-protein signalingincluding: Gs isoforms, Gi isoforms, Go isoforms, G11 isoforms, G12isoforms, G13 isoforms, and Gz isoforms.

II. OTHER EMBODIMENTS OF THE INVENTION

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

The present invention provides a pharmaceutical composition furthercomprising additional therapeutic agent(s). In a preferred embodiment,the present invention provides pharmaceutical composition, wherein theadditional therapeutic agent is, for example, angiotensin convertingenzyme (ACE) inhibitor, β-adrenergic receptor blocker, neprilysininhibitor, diuretic, aldosterone antagonist, Ca2+ channel blocker,nitrates and/or digitalis compound.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with angiotensin II biased agonism activity, or β-Arrestinagonism of the angiotensin II receptor, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

Examples of diseases or disorders associated with the activity of theAT1R and AII, or β-Arrestin agonists of the Angiotensin II Receptor,that can be prevented, modulated, or treated according to the presentinvention include, but are not limited to heart failure such as acutedecompensated heart failure (ADHF), chronic heart failure, fibrosis,atrial fibrillation, coronary artery disease, peripheral vasculardisease, atherosclerosis, renal disease, diabetes, obesity, metabolicsyndrome, hypertension, pulmonary hypertension, cerebrovasculardisorders and the sequelae thereof, cardiovascular disorders, angina,ischemia, stroke, myocardial infarction, acute coronary syndrome,reperfusion injury, angioplastic restenosis, vascular complications ofdiabetes and obesity.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure, coronary artery disease,cardiomyopathy, atrial fibrillation, and related conditions includingbut not limited to acute coronary syndrome, myocardial ischemia,hypertension, atherosclerosis, pulmonary hypertension, peripheralarterial disease, ischemia/reperfusion injury, angina, renal disease,

Examples of diseases or disorders associated with the activity of thebiased agonism, or β-Arrestin agonism of the angiotensin II receptor,that can be prevented, modulated, or treated and/or prophylaxisaccording to the present invention include, but are not limited toHFpEF, HFrEF, and renal disease.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure with preserved ejectionfraction, heart failure with reduced ejection fraction, and renaldisease, comprising administering to a patient in need of such treatmentand/or prophylaxis a therapeutically effective amount of at least one ofthe compounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of renal disease, comprising administeringto a patient in need of such treatment and/or prophylaxis atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure with preserved ejectionfraction, comprising administering to a patient in need of suchtreatment and/or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention, alone, or,optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of reduced ejection fracton heart failure,comprising administering to a patient in need of such treatment and/orprophylaxis a therapeutically effective amount of at least one of thecompounds of the present invention, alone, or, optionally, incombination with another compound of the present invention and/or atleast one other type of therapeutic agent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment and/orprophylaxis of multiple diseases or disorders associated with biasedagonism, or β-Arrestin agonism of the angiotensin II receptor.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment and/or prophylaxis of multiple diseases or disordersassociated with biased agonism, or β-Arrestin agonism of the AngiotensinII Receptor.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with biased agonism, or β-Arrestin agonism of the angiotensinII receptor, comprising administering to a patient in need thereof atherapeutically effective amount of a first and second therapeuticagent, wherein the first therapeutic agent is a compound of the presentinvention. Preferably, the second therapeutic agent, for example ACEi(e.g. enalapril) or a selected inotropic agent such as β-adrenergicagonist (for example dobutamine) or other therapeutically relevant agentthat elevates natriuretic peptide levels such as a neprilysin inhibitor(for example, sacubitril).

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment and/or prophylaxis of multiple diseases or disordersassociated with AT1R and angiotensin II.

In another embodiment compounds within the present invention may beutilized alone or in combination with additional therapeutic agentsdescribed herein for the treatment of various conditions associated withheart failure: heart failure with reduced ejection fraction, heartfailure with preserved ejection fraction, acute decompensated heartfailure, fibrotic disease. Additionally the compounds presented withinthe present invention may be used alone or in combination withadditional therapeutic agents described herein as either acute,sub-acute or chronic therapy.

Where desired, the compound of the present invention may be used incombination with one or more other types of cardiovascular agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of cardiovascular agents that may beoptionally employed in combination with the biased agonist of theangiotensin II receptor of the present invention may be one, two, threeor more cardiovascular agents administered orally in the same dosageform, in a separate oral dosage form, or by injection to produce anadditional pharmacological benefit.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents:anti-hypertensive agents, ACE inhibitors, mineralocorticoid receptorantagonists, calcium channel blockers, β-adrenergic receptor blockers,diuretics, vasorelaxation agents such as nitrates, inotropic agents,digitalis compounds, anti-atherosclerotic agents, anti-dyslipidemicagents, anti-diabetic agents, anti-hyperglycemic agents,anti-hyperinsulinemic agents, anti-thrombotic agents, anti-retinopathicagents, anti-neuropathic agents, anti-nephropathic agents, anti-ischemicagents, anti-obesity agents, anti-hyperlipidemic agents,anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents,anti-restenotic agents, anti-pancreatic agents, lipid lowering agents,anorectic agents, memory enhancing agents, anti-dementia agents,cognition promoting agents, appetite suppressants, agents for treatingheart failure, agents for treating peripheral arterial disease, agentsfor treating malignant tumors, and anti-inflammatory agents.

In another embodiment, additional therapeutic agent(s) used in combinedpharmaceutical compositions or combined methods or combined uses, areselected from one or more, preferably one to three, of the followingtherapeutic agents in treating heart failure: ACE inhibitors,β-blockers, diuretics, mineralocorticoid receptor antagonists, renininhibitors, calcium channel blockers, nitrates, digitalis compounds,inotropic agents, APJ receptor agonists, relaxin receptor agonists,formyl peptide receptor 2 agonists/biased agonists, nitroxyl donors andneprilysin inhibitors.

The present invention may be embodied in other specific forms withoutparting from the spirit or essential attributes thereof. This inventionencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also understoodthat each individual element of the embodiments is its own independentembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment.

III. CHEMISTRY

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or Z- and E-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For examples, “C₁ to C₁₂alkyl” or “C₁₋₁₂ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ alkyl groups; “C₄ to C₁₈alkyl” or “C₄₋₁₈ alkyl” (or alkylene), is intended to include C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₋₄, C₁₅, C₁₆, C₁₇, and C₁₈ alkylgroups. Additionally, for example, “C₁ to C₆ alkyl” or “C₁₋₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl group can beunsubstituted or substituted with at least one hydrogen being replacedby another chemical group. Example alkyl groups include, but are notlimited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene” isused, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

When the term “hydrocarbon chain” is used, it is intended to include“alkyl”, “alkenyl” and “alkynyl”, unless otherwise specified.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. Forexample, “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intendedto include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), and t-butoxy. Similarly, “alkylthio” or“thioalkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample methyl-S— and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. For example, “C₃ to C₆ cycloalkyl” or“C₃₋₆ cycloalkyl” is intended to include C₃, C₄, C₅, and C₆ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”. Theterm “cycloalkenyl” refers to cyclized alkenyl groups. C₄₋₆ cycloalkenylis intended to include C₄, C₅, and C₆ cycloalkenyl groups. Examplecycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, and cyclohexenyl.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic hydrocarbon ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, itis intended to include “aryl.” A bridged ring occurs when one or more,preferably one to three, carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or bicyclic aromatic hydrocarbons,including, for example, phenyl, and naphthyl. Aryl moieties are wellknown and described, for example, in Lewis, R. J., ed., Hawley'sCondensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc.,New York (2007). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 1,3-dioxol-2-one,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,imidazolopyridinyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted.

The nitrogen atom is substituted or unsubstituted (i.e., N or NR whereinR is H or another substituent, if defined). The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2).

Examples of 5- to 6-membered heteroaryls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. et al., Protecting Groups in Organic Synthesis, 4th Edition,Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981), the disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: (1) acyl types such as formyl,trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamatetypes such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are formed between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Compounds of the Formula (I) and/or the Examples herein may in somecases form salts which are also within the scope of this invention.Reference to a compound of the Formula (I) and/or Examples herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic and/orbasic salts formed with inorganic and/or organic acids and bases.Zwitterions (internal or inner salts) are included within the term“salt(s)” as used herein (and may be formed, for example, where the Rsubstituents comprise an acid moiety such as a carboxyl group). Alsoincluded herein are quaternary ammonium salts such as alkylammoniumsalts. Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are useful, forexample, in isolation or purification steps which may be employed duringpreparation. Salts of the compounds of the Formula (I) may be formed,for example, by reacting a compound I with an amount of acid or base,such as an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization. As usedherein, “pharmaceutically acceptable salts” refer to derivatives of thedisclosed compounds wherein the parent compound is modified by makingacid or base salts thereof. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic groups such as amines; and alkali or organic salts of acidicgroups such as carboxylic acids. The pharmaceutically acceptable saltsinclude the conventional non-toxic salts or the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, such conventional non-toxicsalts include those derived from inorganic acids such as hydrochloric,hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the saltsprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, and isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, Jr., L. V.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

“Base addition salt” refers to those salts which retain the biologicaleffectiveness and properties of the free acids, which are notbiologically or otherwise undesirable. These salts are prepared fromaddition of an inorganic base or an organic base to the free acid. Saltsderived from inorganic bases include, but are not limited to, thesodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc,copper, manganese, aluminum salts and the like. In one aspect, inorganicsalts are the ammonium, sodium, potassium, calcium, and magnesium salts.Salts derived from organic bases include, but are not limited to, saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins and the like. In anotheraspect, organic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

“Acid addition salts” and “base addition salts” which are notpharmaceutically acceptable may be useful in the preparation and/orpurification of the compounds.

The present invention is intended to cover the compounds in theirneutral state, salts of those compounds, or mixtures of the compounds intheir neutral state with one or more salt forms, or mixtures of saltforms.

In addition, compounds of Formula (I) may have prodrug forms. Anycompound that will be converted in vivo to provide the bioactive agent(i.e., a compound of Formula (I)) is a prodrug within the scope andspirit of the invention. Various forms of prodrugs are well known in theart. For examples of such prodrug derivatives, see:

a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and Widder,K. et al., eds., Methods in Enzymology, 112:309-396, Academic Press(1985);

b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design andDevelopment, pp. 113-191, Harwood Academic Publishers (1991);

c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);

d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);

e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and

f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods andPrinciples in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield Formula (I) compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of Formula (I) includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced(2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism.Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich,Switzerland (2003); Wermuth, C. G., ed., The Practice of MedicinalChemistry, 3rd Edition, Academic Press, San Diego, Calif. (2008).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates.

Other Definitions

Abbreviations as used herein, are defined as follows: “1 x” for once, “2x” for twice, “3 x” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or min, “h” forhour or h, “rt” for room temperature, “RT” for retention time, “atm” foratmosphere, “psi” for pounds per square inch, “conc.” for concentrate,“aq” for “aqueous”, “sat” or “sat′d” for saturated, “MW” for molecularweight, “mp” for melting point, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC”or “tlc” for thin layer chromatography, “NMR” for nuclear magneticresonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, “Z” and “ee” arestereochemical designations familiar to one skilled in the art.

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

The compounds of Formula (I) may be prepared by the exemplary processesdescribed in the following schemes and working examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working examples. Protection and de-protection inthe processes below may be carried out by procedures generally known inthe art (see, for example, Wuts, P. G. M. et al., Protecting Groups inOrganic Synthesis, 4th Edition, Wiley (2007)). General methods oforganic synthesis and functional group transformations are found in:Trost, B. M. et al., eds., Comprehensive Organic Synthesis: Selectivity,Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, NewYork, N.Y. (1991); Smith, M. B. et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure. 6th Edition, Wiley &Sons, New York, N.Y. (2007); Katritzky, A. R. et al, eds., ComprehensiveOrganic Functional Groups Transformations II, 2nd Edition, ElsevierScience Inc., Tarrytown, N.Y. (2004); Larock, R. C., ComprehensiveOrganic Transformations, VCH Publishers, Inc., New York, N.Y. (1999),and references therein.

Imidazolone biphenyl compounds with general structure IX may be preparedaccording to the synthetic scheme shown below. Thus, a functionalizedimidazolone is alkylated with benzyl bromide VI using a base such asK₂CO₃ to form a boronate with general structure VII. Boronate VII isthen reacted with a phenylbromide with general structure VIII in aSuzuki reaction using conditions such as 2M K₃PO₄, dioxane, PdCl₂(dppf)₂at 100° C. to form imidazolone biphenyl compounds with general structureIX.

Imidazole biphenyl compounds with general structure XII, XIII and XIVmay be prepared with the following scheme. Thus, a functionalizedimidazole is alkylated with benzyl bromide VI using a base such as K₂CO₃to form a boronate with general structure XI. Boronate XI is thenreacted with phenyl bromide with general structure VIII in a Suzukireaction using conditions such as 2M K₃PO₄, dioxane, PdCl₂(dppf)₂ at100° C. to form biphenyl compounds with general structure XII. When R3is an ester, the ester may be hydrolyzed using NaOH in MeOH at 60° C. toform the free acid XIII. Free acid XIII may then be converted to anamide using T3P, Hunig's base, NHR₂ in DMF to form secondary andtertiary amides or CDI and NH₄OH to form the primary amide.

Biphenyl alpha-amido carboxylic acid with general structure XVIII may beprepared with the following scheme. Thus, a functionalized alpha-amidoester with general structure XV may be alkylated with benzyl bromide VIusing a base such as K₂CO₃ to form a boronate with general structureXVI. Alkylated alpha-amido ester XVI may then be reacted with aphenylbromide with general structure VIII in a Suzuki reaction usingconditions such as 2M K₃PO₄, dioxane, PdCl₂(dppf)₂ at 100° C. to formcompounds with general structure XVII. The ester may be hydrolyzed usingNaOH in MeOH at 60° C. to form the free acid with general structureXVIII.

Biphenyl tetrazoles with general structure XXII and biphenyloxadiazolones with general structure XXIII may be prepared with thefollowing scheme. Thus, boronates with general structure XIX may bereacted with a bromophenyl nitrile with general structure XX in a Suzukireaction using conditions such as 2M K₃PO₄, dioxane, PdCl₂(dppf)₂ at100° C. to form biphenyl nitrile with general structure XXI. Thebiphenyl nitrile may then be reacted with TMS-azide, dibutyltin oxide intoluene at 100° C. to form biphenyl tetrazole with general structureXXII. The biphenyl nitrile may also be reacted with KOt-Bu,hydroxylamine hydrochloride in THF, followed by CDI to form biphenyloxadiazolone with general structure XXIII.

Biphenyl acids with general structure XXVII may be prepared according tothe following scheme. Thus, boronates with general structure XIX may bereacted with a bromophenyl ester with general structure XXIV in a Suzukireaction using conditions such as 2M K₃PO₄, dioxane, PdCl₂(dppf)₂ at100° C. to form biphenyl ester with general structure XXV. The biphenylester may then be hydrolyzed with NaOH in MeOH at 100° C. to formbiphenyl acid with general structure XXVI.

Imidazopyridines may be prepared according the synthetic scheme shownbelow. Thus, a functionalized amidine XXVII is condensed with diketoneXXVIII to afford the desired pyridine XXIX. This core then undergoes anoxidative cyclization followed by condensation with an acid derivativeto furnish the imidazopyridine XXXI. This imidazopyridine is thenalkylated with a boronic ester intermediate VI to give boronic esterXXXII. Subsequent Suzuki cross coupling with substituted arene VIIIaffords biaryl XXXIII.

General synthetic pathway to access to the biarylacid imidazopyridineanalogs: The imidazopyridine headpiece previously synthesized can alsobe alkylated with an aryl bromide which allows for Suzuki cross-couplingwith a variety of substituted boronic acids containing a protectedt-butyl-sulfonamide moiety. The t-butyl group can be subsequentlyremoved to allow for further functionalization of the sulfonamide, thusproviding the examples shown below.

Compounds in which the Z-G group is an N-linked 1,2,3-triazole can besynthesized using the route shown in the scheme below:

Compounds in which the Z-G group is a C-linked 1,2,3-triazole can besynthesized using the route shown in the scheme below:

Benzimidazole compounds with general structure XL and XLI may beprepared with the following scheme. Thus, benzimidazole XXXIV isalkylated with benzyl bromide XXXV using a base such as K₂CO₃ to form aboronate XXXVI. Boronate XXXVI is then reacted with iodobenzonitrileXXXVII in a Suzuki reaction using conditions such as 2M K₃PO₄, dioxane,PdCl₂(dppf)₂ at 100° C. to form biphenyl compound XXXVIII.

For analogs in which Z-G is a substituted 2-pyridyl group, XXXVIII isreacted with BisPIN Pd₂(dba)₃ and Xphos in dioxane at 100° C. to form aboronate which is then reacted with a substituted 2-pyridyl bromideZ-G-Br using conditions such as PdCl₂(dppf)₂ and 2M K₃PO₄ in dioxane, at100° C. to form nitrile XXXIX.

For analogs in which Z-G is not a substituted 2-pyridyl group, XXXVIIIis reacted with a boronate or boronic acid Z-G-B(OR)₂ using conditionssuch as PdCl₂(dppf)₂ and 2M K₃PO₄ in dioxane, at 100° C. to form nitrileXXXIX.

Nitrile XXXIX can then be reacted with Bu₃SnCl, NaN₃ in xylenes at 140°C. followed by NaOH in MeOH/THF at 65° C. to form compounds with generalstructure XL. Alternatively, XXXIX can be reacted with BMIM[OAc],hydroxylamine HCl at 50° C. followed by NaOH in MeOH/THF at 65° C. toform compounds with general structure XLI.

EXAMPLES

The following compounds of the invention have been prepared, isolatedand characterized using the methods disclosed herein. They demonstrate apartial scope of the invention and are not meant to be limiting of thescope of the invention. In the experimental procedures, solution ratiosexpress a volume relationship, unless stated otherwise. NMR chemicalshifts (δ) are reported in parts per million (ppm). Products werepurified by reverse phase preparative HPLC and analyzed by reverse phaseanalytical LC-MS and HPLC using the following methods:

Method A1: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7-μmparticles; Mobile Phase A: 5:95 ACN:H₂O with 10 mM NH₄OAc; Mobile PhaseB: 95:5 ACN:H₂O with 10 mM NH₄OAc; Temperature: 50° C.; Gradient: 0-100%B over 3 minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min;Detection: MS and UV at 220 nm.

Method A2: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 μm particles;Mobile Phase A: H₂O with 0.05% TFA; Mobile Phase B: ACN with 0.05% TFA;Gradient: 2-98% B over 1 minute, then a 0.5 minute hold at 98% B; Flow:0.8 mL/min; Detection: MS and UV at 220 nm.

Method A3: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 ACN:H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN:H₂O with 10 mM NH₄OAc; Temperature: 50° C.; Gradient: 0% B to 100% Bover 3 min, then a 0.75 min hold at 100% B; Flow: 1 mL/min; Detection:MS and UV (220 nm).

Method A4: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 ACN:H₂O with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 ACN:H₂O with 0.1% trifluoroacetic acid; Temperature: 50°C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm).

Method A5: Column: Phenomenex Luna C18 4.6×50 mm: Mobile Phase A: 10:90MeOH:H₂O with 0.1% trifluoroacetic acid; Mobile Phase B: 90:10 MeOH:H₂Owith 0.1% trifluoroacetic acid; Gradient: 0% B to 100% B over 2 min,then a 1 min hold at 100% B; Flow: 4 mL/min; Detection: MS and UV (220nm).

Method B: Column Zorbax XDB-C18, 4.6×30 mm, 3.5 micron; Mobile Phase A:5/95/0.05 MeOH/H₂O/TFA; Mobile Phase B: 95/5/0.05 MeOH/H₂O/TFA,gradient: 100% A to 100% B in 2 min then hold 100% B for 2 min, flowrate 3 mL/min, monitoring absorbance at 220 nm and 254 nm.

Method C: Column: Kinetex C18, 21.2×100 mm, 5 micron; Mobile Phase A:5/95/0.05 MeOH/H₂O/TFA; Mobile Phase B: 95/5/0.05 MeOH/H₂O/TFA.Gradient: 3-minute at 30% B, then 30-100% B over 7 minutes and a5-minute hold at 100% B; Flow: 20 mL/min; stop time at 15 minutes,monitoring absorbance at 220 nm and 254 nm.

Method D: Kinetex C18, 21×100 mm, 5 micron; Mobile Phase A: 5/95/0.1MeOH/H₂O/HCO₂H; Mobile Phase B: 95/5/0.1 MeOH/H₂O/HCO₂H. Gradient: 3minute at 30% B, then 30-100% B over 7 minutes and 5 minutes hold at100% B; Flow: 20 mL/min; stop time 15 minutes, monitoring absorbance at220 nm and 254 nm.

Method E: C18 Phenomenex Luna AXIA column 30×100 mm, 5 micron; MobilePhase A: 10% MeOH— 90% H₂O—0.1% TFA; Mobile Phase B: 90% MeOH— 10%H₂O—0.1% TFA. Gradient: 20-100% B in 10 min; then 100% B in 2 min with aflow rate of 40 mL/min; stop time 12 minutes, monitoring absorbance at220 nm and 254 nm.

Method F: Column: Kinetex C18, 21.2×100 mm, 5 micron; Mobile Phase A:5/95/0.05 MeOH/H₂O/TFA or 5/95/0.1 MeOH/H₂O/HCO₂H; Mobile Phase B:95/5/0.05 MeOH/H₂O/TFA or 95/5/0.1 MeOH/H₂O/HCO₂H. Gradient: 0.5 minuteat 50% B, then 50-100% B over 8 minutes and a 2.5 minutes hold at 100%B; Flow: 20 mL/min; stop time at 11 minutes, monitoring absorbance at220 nm and 254 nm.

Method G: Column: XBridge C18, 19×200 mm, 5 micron; Mobile Phase A: 5:95ACN: H₂O with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂Owith 0.1% trifluoroacetic acid; Gradient: 10-50% B over 19 minutes, thena 5-minute hold at 100% B; Flow: 20 mL/min, monitoring absorbance at 220nm and 254 nm.

Method H: Column Kinetex C18, 3.0×30 mm, 2.6 micron; Mobile Phase A:5/95/0.1 MeOH/H₂O/AcOH; Mobile Phase B: 95/5/0.1 MeOH/H₂O/AcOH.Gradient: 100% A to 100% B over 0.5 min, then hold at 100% B for 1.5min; Flow: 1.5 mL/min; stop time at 2 minutes, monitoring absorbance at220 nm and 254 nm.

Method I: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with10 mM NH₄OAc; Gradient: 11-51% B over 25 minutes, then a 5-minute holdat 100% B; Flow: 20 mL/min

Method J: Column Kinetex-C18, 3.0×30 mm, 2.6 m particles; Mobile PhaseA: 5:95 MeOH:H₂O with 0.1% AcOH; Mobile Phase B: 95:5 MeOH:H₂O with 0.1%AcOH; Gradient: 0-100% B over 2 minutes, flow 1.5 mL/min; Detectorwavelength=220 nm and 254 nm

Common Intermediate I-001:5-bromo-4′-(hydroxymethyl)-[1,1′-biphenyl]-2-carbonitrile

To a solution of (4-(hydroxymethyl)phenyl)boronic acid (400 mg, 2.6mmol), 4-bromo-2-iodobenzonitrile (800 mg, 2.6 mmol) and Pd (PPh₃)₄ (66mg, 0.057 mmol) in THF/MeOH (3:1, 12 ml) was added 1.5 N Na₂CO₃ (2.6 ml,3.9 mmol). The reaction mixture was sealed, placed in a microwavereactor and heated at 120° C. for 60 min LC-MS indicated completion ofreaction. The reaction mixture was diluted with EtOAc/H₂O. The organiclayer was collected, washed with brine, dried over Na₂SO₄ andconcentrated. The crude product was purified by flash chromatography (2%to 60% EtOAc in hexane over 18 min using a 40 g silica gel cartridge).The desired fractions were combined and concentrated to yield I-001 (446mg, 1.5 mmol, 60% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ7.72 (d, J=1.4 Hz, 1H), 7.67-7.60 (m, 2H), 7.60-7.51 (m, 4H), 4.81 (d,J=5.5 Hz, 2H), 1.80 (br t, J=5.8 Hz, 1H). ¹³C NMR (126 MHz, MeOH-d₄) δ148.4, 144.1, 137.1, 136.2, 134.5, 132.3, 130.0, 129.3, 128.5, 119.3,65.1. LC-MS: Waters Aquity BEH C18 2.1×50 mm, 1.7 m; A: 90% H₂O+0.05%TFA; B: 90% ACN+0.05% TFA; wavelength 220 nm; flow rate 0.8 mL/min;gradient time 1.0 min; 2 to 98% B. RT=0.86 min, MS (ESI) m/z: 270.0 and272.0 (M-18)⁺.

Common Intermediate I-002:5-bromo-4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile

To a suspension of I-001 (522 mg, 1.8 mmol) in CH₂Cl₂ (10 ml) at 0° C.was added PBr₃ (0.19 ml, 2.0 mmol) in CH₂Cl₂ (1.0 mL). The reactionmixture was stirred at 0° C. for 15 min, and rt overnight. The mixturewas diluted with CH₂Cl₂ and poured into a stirred ice-cold sat. NaHCO₃solution. The organic layer was collected, washed with brine, dried overNa₂SO₄ and concentrated to yield I-002 (574 mg, 1.6 mmol, 90% yield) asa white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (dd, J=1.5, 0.7 Hz, 1H),7.64-7.58 (m, 2H), 7.53 (s, 4H), 4.54 (s, 2H).

Common Intermediate I-003:(6′-(2-trityl-2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methanol

Intermediate I-003A: 3-bromo-[1,1′-biphenyl]-4-carbonitrile

To a solution of 3-amino[1,1′-biphenyl]-4-carbonitrile (22 g, 113 mmol)in ACN (250 mL) was added copper(II) bromide (0.253 g, 1.133 mmol), CSA(31.6 g, 136 mmol), tetrabutylammonium bromide (73.0 g, 227 mmol) andtert-butyl nitrite (17.96 mL, 136 mmol) dropwise and the reactionmixture was stirred at 60° C. overnight. On the next day, the reactionmixture was filtered over celite, washed with EtOAc (100 ml) and thefiltrate was concentrated. H₂O (500 ml) was added to the crude residue,followed by extraction with EtOAc (3×300 ml). The combined organiclayers were washed with water (400 ml), brine (300 ml), dried oversodium sulfate and concentrated. The crude product was purified bysilica gel chromatography and eluted with 30% EtOAc in petroleum ether.The desired fractions were concentrated to give the desired productI-003A (20.5 g, 74.7 mmol, 65.9% yield) as a white solid. ¹H NMR (400MHz, DMSO-d₆) 8.20 (d, J=1.6 Hz, 1H), 8.027 (d, J=8 Hz, 1H), 7.92-7.89(m, 1H), 7.81-7.79 (m, 2H), 7.55-7.48 (m, 3H).

Intermediate I-003B: methyl6′-cyano-[1,1′:3′,1″-terphenyl]-4-carboxylate

In a flask charged with a stirring bar, a solution of I-003A (19 g, 73.6mmol), (4-(methoxycarbonyl)phenyl)boronic acid (15.90 g, 88 mmol) andpotassium phosphate, tribasic (73.6 mL, 147 mmol) in 1,4-dioxane (250mL) was purged with N₂ for 10 min. Thenbis(triphenylphosphine)palladium(II) chloride (5.17 g, 7.36 mmol) wasadded, and the mixture was again purged with N₂ for 5 min. The mixturewas heated at 100° C. for 5 h. The reaction mixture was cooled to RT,filtered over celite bed, washed with EtOAc (100 ml) and concentrated togive the crude residue, to which H₂O (500 ml) was added, stirred for 15min, filtered and dried to give the crude product. The crude product wastriturated with MTBE (100 ml) and the solid obtained was stirred for 15min, filtered and dried to get the product which was slightly black incolor. The product was dissolved in THF and was treated with charcoal at60° C., filtered and concentrated to give the desired I-003B (18 g, 57.4mmol, 78% yield) as a yellow solid. ¹H NMR (500 MHz, CDCl₃) 8.27-8.15(m, 2H), 7.93-7.84 (m, 1H), 7.78-7.70 (m, 4H), 7.68-7.63 (m, 2H),7.58-7.43 (m, 3H), 3.99 (s, 3H).

Intermediate I-003C: methyl6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-carboxylate

A solution of I-003B (7.5 g, 23.93 mmol), TMS-N₃ (15.88 mL, 120 mmol)and dibutyltin oxide (5.96 g, 23.93 mmol) in toluene (175 mL) was heatedin a sealed tube at 100° C. overnight. Methanol (20 ml) was first addedto the reaction and the resulting solution was diluted with EtOAc. Tothis organic phase was added ceric ammonium nitrate (75 g dissolved in 1L of H₂O) dropwise and with swirling until bubbling ceased (N₂ gasevolution). To the mixture was added sat. NH₄Cl solution (250 ml) andthen it was extracted with EtOAc (150 ml×3). The combined organic layerswere washed with H₂O (500 ml), brine (400 ml), dried over sodiumsulphate, and concentrated to give the crude product. The crude productwas triturated with MTBE (150 ml) and the solid obtained was stirred for30 min, filtered, washed with MTBE (50 ml) and dried to give the I-003C(7.25 g, 18.43 mmol, 77% yield) as the product. ¹H NMR (500 MHz,MeOH-d₄) δ 8.01 (d, J=8.3 Hz, 2H), 7.92-7.87 (m, 1H), 7.86-7.81 (m, 2H),7.77 (d, J=7.7 Hz, 2H), 7.58-7.49 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.35(d, J=8.5 Hz, 2H), 3.93 (s, 3H);); LC-MS: method A2, Rt=0.89 min, MS(ESI) m/z: 357.10 (M+H)⁺.

Intermediate I-003D: methyl6′-(2-trityl-2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-carboxylate

To a solution of I-003C (14.5 g, 40.7 mmol) and TEA (11.34 mL, 81 mmol)in DCM (200 mL) was added trityl-Cl (17.01 g, 61.0 mmol) and thereaction mixture was stirred at RT overnight. To the reaction mixtureH₂O (300 ml) was added and extracted with DCM (2×200 ml). The combinedorganic layers was washed with H₂O (300 ml), brine (200 ml), dried oversodium sulphate and concentrated to get the crude product. The crudeproduct was triturated with MeOH (300 ml) and the solid obtained wasstirred for 30 min, filtered, washed with MeOH (100 ml) and dried togive I-003D (22 g, 34.5 mmol, 85% yield) as the product. ¹H NMR (500MHz, CDCl₃) δ 8.14 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.3 Hz, 2H), 7.76 (dd,J=8.1, 1.8 Hz, 1H), 7.68 (d, J=7.4 Hz, 2H), 7.63 (d, J=1.7 Hz, 1H),7.52-7.46 (m, 2H), 7.44-7.40 (m, 1H), 7.38-7.16 (m, 11H), 6.93 (d, J=7.7Hz, 7H), 3.96 (s, 3H).

Common Intermediate I-003

I-003D (1 g, 1.670 mmol) was dissolved in THF (20 mL). Methanol (0.135mL, 3.34 mmol) was added at 0° C. followed by 2M lithium borohydride inTHF (1.670 mL, 3.34 mmol). The reaction was allowed to stir at 40° C.overnight. The reaction was quenched with ˜10 mL of H₂O at 0° C. andallowed to stir at RT for 3 hours. The reaction mixture was thenextracted with EtOAc (3×) and the combined organic layer was washed withbrine, dried with sodium sulfate, filtered and concentrated. The residuewas purified on 80 g silica gel cartridge on ISCO, which was eluted witha 30 min gradient of 0-100% EtOAc in hexane. The desired fraction wasevaporated to give Common Intermediate I-003 (0.736 g, 1.290 mmol, 77%yield) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (s, 1H),7.73-7.68 (m, 1H), 7.64 (d, J=6.2 Hz, 3H), 7.46 (s, 2H), 7.40-7.24 (m,10H), 7.21-7.16 (m, 2H), 7.14 (s, 2H), 6.94-6.81 (m, 6H), 4.59 (d, J=5.9Hz, 2H).

Common Intermediate I-004:5-(4″-(bromomethyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2-trityl-2H-tetrazole

To an ice-cold mixture of(6′-(2-trityl-2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methanol

(Intermediate I-003, 0.750 g, 1.31 mmol) in DCM (15 mL) was addedtriphenylphosphine (0.479 g, 1.45 mmol) and 2,6-dimethylpyridine (0.169g, 1.58 mmol). To this mixture was added carbon tetrabromide (0.470 g,1.45 mmol) in one portion and the reaction mixture was stirred for 15min. The volatiles were then evaporated while maintaining a pottemperature of 0° C. The oily residue was dissolved in DCM (5 ml), aminimum volume of hexane was added and the resulting slightly turbidmixture was applied to a 40 gram ISCO-type silica gel column. Flashchromatography (0 to 30% EtOAc/hexane gradient) then afforded the titlecompound (0.760 g, 1.20 mmol, 91% yield) as a white solid. ¹H NMR(CDCl₃) δ ppm 8.08 (d, J=7.8 Hz, 1H), 7.71 (dd, J=8.0, 1.8 Hz, 1H),7.59-7.68 (m, 3H), 7.42-7.49 (m, 2H), 7.31-7.41 (m, 4H), 7.23-7.31 (m,6H), 7.11-7.18 (m, 4H), 6.88-6.95 (m, 6H), 4.40 (s, 2H).

Common Intermediate I-005: methyl2-ethoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-7-carboxylate

To a solution of methyl 2-ethoxy-1H-benzo[d]imidazole-7-carboxylate(1.00 g, 4.54 mmol) in 2-propanol (15 ml) was added potassium carbonate(1.26 g, 9.08 mmol) and this was stirred at 30° C. for 5 minutes. Tothis mixture were added2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.44g, 4.77 mmol) and tetrabutylammonium iodide (0.084 g, 0.227 mmol) andthe temperature was increased to 45° C. After stirring for 2.5 hours,another portion of2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.250g, 0.842 mmol) was added and the reaction was stirred for an additional18 hours. The reaction was cooled to RT and diluted with EtOAc (200 ml),and H₂O (50 ml) was added. The layers were separated and the organiclayer was washed with brine (50 ml), then dried over anhydrous sodiumsulfate, filtered, and evaporated under reduced pressure. The residuewas dissolved in DCM (10 ml) and injected on a 40-gram ISCO-type silicagel column pre-equilibrated with hexane and the title compound waspurified by elution using a 0 to 60% EtOAc/hexane gradient to providethe title compound as a yellow solid. (1.44 g, 3.31 mmol, 72% yield).LC-MS (Method H): 1.42 min, [M+H]⁺=437.2; ¹H NMR (400 MHz, CDCl₃) δ ppm7.73 (dd, J=8.0, 1.0 Hz, 1H) 7.67 (m, J=8.2 Hz, 2H) 7.53 (dd, J=7.8, 1.2Hz, 1H) 7.16 (t, J=7.8 Hz, 1H) 6.96 (m, J=8.2 Hz, 2H) 5.63 (s, 2H) 4.65(q, J=7.0 Hz, 2H) 3.72 (s, 3H) 1.46 (t, J=7.0 Hz, 3H) 1.31 (s, 12H).

Example 001:3-((6′-(2H-tetrazol-5-yl)-2″-(trifluoromethoxy)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 001a: 2-amino-4,6-dimethylnicotinamide

The title compound was prepared from 3-amino-3-iminopropanamidehydrochloride (1.376 g, 10 mmol) and pentane-2,4-dione (1.073 mL, 10.50mmol) according to the procedure described in J. Med. Chem. 2007, 50,828. The crude was purified by ISCO (DCM/MeOH, 0-20%) to afford 001a(1.54 g, 9.32 mmol, 93% yield) as a white solid. LC-MS (Method A2): 0.32min, [M+H]⁺=166.0; ¹H NMR (400 MHz, MeOD) δ ppm 6.43 (s, 1H), 2.28 (s,3H), 2.28 (s, 3H).

Intermediate 001b: 5,7-dimethyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

A solution of 2-amino-4,6-dimethylnicotinamide (001a, 0.470 g, 2.85mmol) in MeOH (14.2 mL) was treated with potassium hydroxide (0.559 g,9.96 mmol) and iodobenzene diacetate (1.375 g, 4.27 mmol) as describedin J. Med. Chem. 2011, 54, 4219. The crude was purified by ISCO(DCM/MeOH, 0-20%) to afford the title compound as an off-white solid(0.235 g, 1.440 mmol, 50.6% yield). LC-MS (Method A2): 0.42 min,[M+H]⁺=164.1; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.03 (br s, 1H), 10.76(s, 1H), 6.64 (s, 1H), 2.33 (s, 3H), 2.23 (s, 3H).

Intermediate 001c: 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 001b (0.224 g, 1.373 mmol) was treated with propionic acid(1.95 mL, 26.1 mmol), propionic anhydride (1.94 mL, 15.10 mmol) andmagnesium chloride (0.196 g, 2.059 mmol) as described in J. Med. Chem.2007, 50, 828. The crude was purified by ISCO (DCM/MeOH, 0-20%) to yieldthe title compound as a brown oil (0.220 g, 1.130 mmol, 82% yield).LC-MS (Method A2): 0.42 min, [M+H]⁺=176.7; ¹H NMR (400 MHz, MeOD) δ ppm7.05 (s, 1H), 2.98 (q, J=7.6 Hz, 2H), 2.59 (s, 6H), 1.43 (t, J=7.7 Hz,3H).

Intermediate 001d:2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001c (1.2 g, 6.85 mmol) in DMF (41.5 mL)was added sodium hydride (0.498 g, 12.45 mmol) at RT and the reactionwas stirred vigorously for 30 min. Then a solution of2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.849g, 6.23 mmol) in DMF (20.75 mL) was added and the resulting reactionmixture was allowed to stir for 2 h before being quenched with asaturated aqueous solution of NH₄Cl. The mixture was diluted with EtOAcand extracted. The organic phase was dried over MgSO₄, filtered andconcentrated before being purified by ISCO (hexane/EtOAc, 0-100%) toafford the title compound (1.35 g, 3.45 mmol, 55.4% yield) as a lightyellow solid. LC-MS (Method A2): 0.81 min, [M+H]⁺=392.4; ¹H NMR (500MHz, CDCl₃) δ ppm 7.71 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 6.88(s, 1H), 5.46 (s, 2H), 2.74 (q, J=7.5 Hz, 2H), 2.63 (s, 3H), 2.57 (s,3H), 1.31 (s, 12H), 1.27 (t, J=7.6 Hz, 3H).

Intermediate 001e: 2-bromo-4-nitrobenzonitrile

A solution of 4-nitrobenzonitrile (1.0 g, 6.75 mmol) in DCE (27.0 mL)was treated with NBS (1.322 g, 7.43 mmol), CSA (0.784 g, 3.38 mmol) anddiacetoxypalladium (0.152 g, 0.675 mmol) according to the proceduredescribed in JOC, 2013, 78, 2786. After 16 h at 70° C., LC-MS analysisonly showed about 60% conversion. Another portion of diacetoxypalladium(0.152 g, 0.675 mmol) was added along with NBS (0.5 eq., 0.600 g) andthe reaction mixture was reheated at 70° C. for 7.5 h. The cooledreaction mixture was diluted with DCM, washed with 1.5 M aqueous K₂HPO₄,followed by saturated aqueous NH₄Cl. The organic phase was dried overMgSO₄, filtered, concentrated and purified by ISCO (Hexanes/EtOAc,0-100%) to afford the title compound Intermediate 001e (1.01 g, 4.45mmol, 65.9% yield) as a white solid. LC-MS (Method A2): 0.82 min, [M+H]No ion observed; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.56 (d, J=2.2 Hz, 1H),8.29 (dd, J=8.6, 2.2 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H).

Intermediate 001f:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-nitro-[1,1′-biphenyl]-2-carbonitrile

A mixture of Intermediate 001d (0.670 g, 1.712 mmol) and Intermediate001e (0.466 g, 2.055 mmol) in dioxane (11.4 mL) was treated with K₃PO₄(2M aq., 2.14 ml, 4.28 mmol) followed by PdCl₂(dppf) (0.125 g, 0.171mmol). The resulting mixture was degassed with N₂ for 2 min before thereaction vessel was sealed and heated at 100° C. overnight. The cooledreaction mixture was concentrated to dryness and the residue purified byISCO (Hexanes/AcOEt, 0-100%) to afford the title compound (Intermediate001f, 0.540 g, 1.312 mmol, 77% yield) as an amber oil. LC-MS (MethodA2): 0.79 min, [M+H]⁺=412.2; ¹H NMR (500 MHz, CDCl₃) δ ppm 8.33 (d,J=2.2 Hz, 1H), 8.27 (dd, J=8.4, 2.3 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H),7.53 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 6.92 (s, 1H), 5.55 (s,2H), 2.83 (q, J=7.4 Hz, 2H), 2.64 (s, 3H), 2.60 (s, 3H), 1.35 (t, J=7.6Hz, 3H).

Intermediate 001 g:2-ethyl-5,7-dimethyl-3-((5′-nitro-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001f (0.250 g, 0.608 mmol) in toluene (6.1mL) was added dibutyltin oxide (0.151 g, 0.608 mmol) and TMS-N₃ (0.403mL, 3.04 mmol). Then the reaction vessel was sealed and the mixture washeated at 110° C. overnight behind a blast shield (according to theprocedure described in J. Org. Chem, 1993, 58, 4139). After cooling, thereaction mixture was diluted with MeOH and EtOAc and quenched by theportionwise addition of a 10% aqueous solution of CAN (16.700 g, 3.05mmol) until bubbling ceased. The resulting mixture was stirred at RT for30 min, then partitioned with saturated aqueous NH₄Cl and EtOAc. Theorganic phase was dried over MgSO₄, filtered and concentrated to give ayellow foam which was purified by ISCO (DCM/MeOH, 0-20%) to afford thetitle compound as a light yellow foam (0.250 g, 0.550 mmol, 91% yield).LC-MS (Method A2): 0.71 min, [M+H]⁺=455.3; ¹H NMR (400 MHz, CDCl₃) δ ppm8.37-8.19 (m, 2H), 8.08 (br. s., 1H), 7.18-7.10 (m, 2H), 7.08-7.02 (m,2H), 6.97 (s, 1H), 5.50 (s, 2H), 2.77 (q, J=7.2 Hz, 2H), 2.60 (s, 3H),2.48 (s, 3H), 1.05 (t, J=7.4 Hz, 3H).

Intermediate 001 h:2-ethyl-5,7-dimethyl-3-((5′-nitro-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001 g (1.6 g, 3.52 mmol) in DCM (17.6 mL)at RT was added triethylamine (0.638 mL, 4.58 mmol) followed by tritylchloride (1.030 g, 3.70 mmol). After 20 min, the reaction mixture wasquenched with few drops of MeOH, diluted with DCM and washed with 1 Maqueous K₂HPO₄. The organic phase was dried over MgSO₄, filtered andconcentrated. A quantitative yield was assumed and the product was takento the subsequent reduction step without further purification. LC-MS(Method A2): 1.06 min, [M+H]⁺=697.1.

Intermediate 001i:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-amine

Intermediate 001 h (2.15 g, 3.09 mmol) was diluted in THF (61.7 mL) andtreated with Pd—C (Degussa) (0.328 g, 0.309 mmol). The resultingsuspension was purged with H₂ (3× flask volume, approximatively 1.5 L)and allowed to stir under a balloon atmosphere of H₂ overnight. Thereaction mixture was then diluted with EtOAc, filtered over Celite andconcentrated. The crude residue was used as such in the next step. LC-MS(Method A2): 0.98 min, [M+H]⁺=667.1; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.75(d, J=8.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.34-7.27 (m, 4H), 7.25-7.17 (m,6H), 7.03 (d, J=8.1 Hz, 2H), 6.90 (dd, J=7.4, 1.7 Hz, 5H), 6.83 (d,J=8.1 Hz, 2H), 6.72 (dd, J=8.6, 2.4 Hz, 1H), 6.58 (d, J=2.2 Hz, 1H),5.33 (s, 2H), 3.86 (s, 2H), 2.70-2.63 (m, 5H), 2.58 (s, 3H), 1.26-1.21(m, 3H).

Intermediate 001j:3-((5′-bromo-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a suspension of Intermediate 001i (1.15 g, 1.725 mmol) in ACN (17.3mL) was added copper (II) bromide (0.501 g, 2.242 mmol) followed byt-butyl nitrite (0.456 mL, 3.45 mmol). The reaction was stirred at RTfor 45 min then diluted with EtOAc (100 mL). The organic phase was thenwashed with 1 M aqueous HCl rapidly followed by 1 M aqueous K₂HPO₄ tore-basify the organic phase. The organic phase was then dried overMgSO₄, filtered, concentrated and purified by ISCO (Hexanes/EtOAc,0-100%). The title compound was isolated as a viscous, pale yellow oil(Intermediate 001j, 0.560 g, 0.766 mmol, 44.4% yield over the three-stepsequence). LC-MS (Method A2): 1.10 min, [M+H]⁺=732.3; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.81 (d, J=8.1 Hz, 1H), 7.60-7.55 (m, 1H), 7.49 (d, J=2.0Hz, 1H), 7.37-7.27 (m, 4H), 7.26-7.19 (m, 5H), 7.02 (d, J=8.1 Hz, 2H),6.96-6.82 (m, 9H), 5.35 (s, 2H), 2.71-2.61 (m, 5H), 2.57 (s, 3H), 1.25(t, J=7.6 Hz, 3H).

Example 001:3-((6′-(2H-tetrazol-5-yl)-2″-(tritluoromethoxy)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001j (0.020 g, 0.027 mmol) and(2-(trifluoromethoxy)phenyl)boronic acid (0.028 g, 0.137 mmol) indioxane (2 mL) was added 2M aqueous K₃PO₄ (0.068 mL, 0.137 mmol)followed by PdCl₂(dppf) (0.002 g, 2.74 mol). The resulting mixture wassparged with N₂ for 2 min before the reaction vessel was sealed andheated at 120° C. for 30 min under microwave irradiation. The reactionmixture was cooled to RT, diluted with EtOAc and filtered over a pad ofCelite/MgSO₄. The filtrate was concentrated to a brown residue which wasdissolved in DCM (2 mL) and treated with triethylsilane (0.022 mL, 0.137mmol) followed by TFA (0.105 mL, 1.369 mmol) for 10 min. The reactionmixture was then concentrated, re-solvated in DMF, filtered thenpurified via preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile PhaseB: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 20-60% B over 20 minutes,then a 5-minute hold at 100% B; Flow: 20 mL/min) to afford 0.0065 g(0.011 mmol, 40% yield) of the title compound Example 001. LC-MS (MethodA2): 0.86 min, [M+H]⁺=570.1; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.76-7.52(m, 5H), 7.51 (br s, 2H), 7.13-6.99 (m, 4H), 6.95 (s, 1H), 5.44 (s, 2H),2.75 (q, J=7.4 Hz, 2H), 2.50-2.47 (m, 6H), 1.19 (t, J=7.4 Hz, 3H).

The following examples have been similarly prepared from Intermediate001j as described above for the synthesis of Example 001. Two analyticalLC-MS injections were used to determine the final purity. The retentiontime of one of them is reported for each compound and is referred asMethod A1 or Method A2.

LC-MS m/z [M + H]⁺; ¹H NMR (500 MHz, DMSO-d₆) Ex Structure MW RT(Method) δ ppm 002

499.61 500.10; 0.83 min (Method A2) 7.70 (d, J = 7.9 Hz, 1H), 7.52 (d, J= 7.8 Hz, 1H), 7.41 (s, 1H), 7.36- 7.25 (m, 4H), 7.13-7.07 (m, 2H), 7.04(d, J = 8.1 Hz, 2H), 6.95 (s, 1H), 5.45 (s, 2H), 2.79-2.71 (m, 3H), 2.55(s, 6H), 2.30 (s, 3H), 1.21 (t, J = 7.4 Hz, 3H) 003

527.66 528.30; 0.90 min (Method A2) 7.72 (d, J = 7.8 Hz, 1H), 7.53- 7.44(m, 2H), 7.43-7.34 (m, 2H), 7.30-7.21 (m, 3H), 7.17 (s, 1H), 7.14-7.08(m, 2H), 7.07 (s, 1H), 5.53 (s, 2H), 3.02 (dt, J = 13.4, 6.8 Hz, 1H),2.93-2.84 (m, 2H), 2.54 (d, J = 2.7 Hz, 6H), 1.20 (t, J = 7.5 Hz, 3H),1.14 (d, J = 6.7 Hz, 6H) 004

485.58 486.10; 0.81 min (Method A2) 7.83-7.74 (m, 3H), 7.73-7.64 (m,2H), 7.53-7.45 (m, 2H), 7.44- 7.36 (m, 1H), 7.13 (d, J = 7.9 Hz, 2H),7.04 (d, J = 7.9 Hz, 2H), 6.95 (s, 1H), 5.45 (s, 2H), 2.77 (d, J = 7.3Hz, 2H), 2.55 (s, 6H), 1.22 (t, J = 7.5 Hz, 3H) 005

515.61 516.10; 0.81 min (Method A2) 006

569.58 570.20; 0.88 min (Method A2) 7.90 (d, J = 8.3 Hz, 2H), 7.82 (d, J= 7.5 Hz, 1H), 7.77-7.66 (m, 2H), 7.46 (d, J = 8.1 Hz, 2H), 7.10 (br s,2H), 7.04 (d, J = 7.5 Hz, 2H), 6.95 (s, 1H), 5.44 (s, 2H), 2.80-2.74 (m,2H), 2.50 (d, J = 2.9 Hz, 6H), 1.20 (t, J = 7.4 Hz, 3H) 007

553.58 554.20; 0.88 min (Method A2) 8.02 (d, J = 7.9 Hz, 2H), 7.91- 7.72(m, 5H), 7.21-7.01 (m, 4H), 6.95 (s, 1H), 5.46 (s, 2H), 2.78 (q, J = 7.3Hz, 2H), 2.51 (br. s., 6H), 1.23 (d, J = 3.1 Hz, 3H) 008

499.61 500.10; 1.800 min (Method A1) 7.79 (d, J = 7.9 Hz, 1H), 7.71 (d,J = 7.9 Hz, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.56 (d, J = 7.6 Hz, 1H),7.37 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 7.9 Hz,2H), 7.05 (d, J = 7.9 Hz, 2H), 6.95 (s, 1H), 5.45 (s, 2H), 2.78 (q, J =7.5 Hz, 2H), 2.55 (s, 6H), 2.38 (s, 3H), 1.27-1.19 (m, 3H) 009

513.64 514.30; 1.970 min (Method A1) 7.79 (d, J = 7.9 Hz, 1H), 7.70 (d,J = 7.9 Hz, 1H), 7.68 (s, 1H), 7.39 (s, 2H), 7.15-7.10 (m, 2H), 7.08-7.01 (m, 3H), 6.95 (s, 1H), 5.46 (s, 2H), 2.77 (q, J = 7.5 Hz, 2H), 2.55(s, 6H), 2.33 (s, 6H), 1.25-1.21 (m, 5H) 010

501.58 502.30; 1.500 min (Method A1) 7.77-7.72 (m, 1H), 7.67 (d, J = 7.9Hz, 1H), 7.64 (s, 1H), 7.38 (d, J = 7.3 Hz, 1H), 7.26 (s, 1H), 7.24-7.18 (m, 1H), 7.15 (s, 1H), 7.13- 7.08 (m, 4H), 7.05 (s, 1H), 6.98 (d, J= 7.9 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 5.53 (s, 2H), 2.88 (q, J = 7.6Hz, 2H), 2.54-2.52 (m, 6H), 1.23-1.20 (m, 3H) 011

556.66 557.00; 1.380 min (Method A1) 7.90-7.82 (m, 3H), 7.78-7.73 (m,2H), 7.51 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 7.9 Hz, 2H), 7.06 (d, J =7.9 Hz, 2H), 6.96 (s, 1H), 5.46 (s, 2H), 3.00 (br s, 3H), 2.95 (br s,3H), 2.77 (q, J = 7.4 Hz, 2H), 2.55 (s, 6H), 1.26-1.19 (m, 3H) 012

491.61 492.40; 1.600 min (Method A1) 7.79 (d, J = 7.6 Hz, 1H), 7.68 (brs, 3H), 7.62 (d, J = 4.9 Hz, 1H), 7.20- 7.15 (m, 1H), 7.13-7.08 (m, 2H),7.08-7.03 (m, 2H), 6.96 (s, 1H), 5.46 (s, 2H), 2.81-2.74 (m, 2H), 2.55(s, 6H), 1.26-1.19 (m, 3H) 013

536.63 537.20; 1.140 min (Method A1) 8.97 (d, J = 2.8 Hz, 1H), 8.55-8.48 (m, 2H), 8.28 (d, J = 8.8 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.06(d, J = 7.9 Hz, 1H), 7.96 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.64 (dd, J= 8.2, 4.2 Hz, 1H), 7.27-7.02 (m, 5H), 5.56 (s, 2H), 2.90 (q, J = 7.2Hz, 2H), 2.51 (br. s., 6H), 1.25 (t, J = 7.4 Hz, 3H) 014

515.61 516.30; 1.640 min (Method A1) 7.82 (d, J = 7.3 Hz, 2H), 7.76 (d,J = 8.5 Hz, 2H), 7.71 (br s, 2H), 7.18-7.07 (m, 3H), 7.07-6.97 (m, 3H),5.49 (s, 2H), 3.81 (s, 3H), 2.81 (q, J = 6.8 Hz, 2H), 2.55 (s, 3H), 2.53(br. s., 3H), 1.24 (t, J = 7.3 Hz, 3H) 015

528.65 529.20; 1.700 min (Method A1) 7.65-7.54 (m, 4H), 7.50 (s, 1H),7.12 (d, J = 8.2 Hz, 2H), 6.99 (d, J = 7.9 Hz, 2H), 6.95 (s, 1H), 6.79(d, J = 8.8 Hz, 2H), 5.43 (s, 2H), 2.93 (s, 6H), 2.78 (q, J = 7.5 Hz,2H), 2.55 (s, 6H), 1.24 (t, J = 7.5 Hz, 3H) 016

536.63 536.90; 1.470 min (Method A1) 9.40 (br s, 1H), 8.51 (br s, 1H),8.19 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 7.7 Hz,3H), 7.59 (d, J = 7.3 Hz, 1H), 7.47 (br s, 1H), 7.15 (br s, 2H), 6.99(d, J = 7.4 Hz, 2H), 6.93 (s, 1H), 5.43 (s, 2H), 2.77 (q, J = 7.3 Hz,2H), 2.55 (s, 6H), 1.22 (t, J = 7.4 Hz, 3H) 017

538.64 539.00; 1.650 min (Method A1) 018

499.61 500.30; 1.750 min (Method A1) 019

503.57 504.10; 0.81 min (Method A2) 7.79-7.69 (m, 2H), 7.66 (t, J = 7.6Hz, 1H), 7.60 (s, 1H), 7.51-7.43 (m, 1H), 7.40-7.29 (m, 2H), 7.15- 7.08(m, 2H), 7.04 (d, J = 8.0 Hz, 2H), 6.95 (s, 1H), 5.45 (s, 2H), 2.81-2.70(m, 2H), 2.55 (s, 6H), 1.22 (t, J = 7.4 Hz, 3H) 020

515.61 516.10; 0.81 min (Method A2) 7.79 (d, J = 7.7 Hz, 1H), 7.73- 7.64(m, 2H), 7.43-7.36 (m, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.28 (br s, 1H),7.14 (d, J = 7.9 Hz, 2H), 7.04 (d, J = 7.9 Hz, 2H), 7.00-6.92 (m, 2H),5.45 (s, 2H), 3.82 (s, 3H), 2.78 (q, J = 7.3 Hz, 2H), 2.55 (s, 6H), 1.23(t, J = 7.4 Hz, 3H) 021

489.57 490.10; 0.66 min (Method A2) 8.26 (s, 1H), 7.96 (s, 1H), 7.68-7.62 (m, 1H), 7.60-7.55 (m, 2H), 7.12-7.06 (m, 2H), 7.02 (d, J = 8.0 Hz,2H), 6.95 (s, 1H), 5.45 (s, 2H), 3.85 (s, 3H), 2.78 (q, J = 7.3 Hz, 2H),2.55 (s, 6H), 1.25 (t, J = 7.4 Hz, 3H) 022

488.59 489.10; 0.77 min (Method A2) 7.95 (s, 1H), 7.72-7.67 (m, 1H),7.66-7.62 (m, 1H), 7.52 (s, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 7.05 (s,2H), 6.92 (s, 1H), 6.37 (br s, 1H), 6.11 (d, J = 2.7 Hz, 1H), 5.51 (s,2H), 3.74 (s, 3H), 2.85 (q, J = 7.4 Hz, 2H), 2.53 (s, 6H), 1.23 (t, J =7.5 Hz, 3H) 023

556.66 557.1; 0.72 min (Method A2) 7.82 (d, J = 7.9 Hz, 1H), 7.76- 7.71(m, 2H), 7.70-7.66 (m, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.53 (t, J = 7.7Hz, 1H), 7.38 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.9 Hz, 2H), 6.99 (d, J= 8.3 Hz, 2H), 6.95 (s, 1H), 5.44 (s, 2H), 3.00 (br. s., 3H), 2.93 (br.s., 3H), 2.79 (q, J = 7.5 Hz, 2H), 2.55 (s, 3H), 2.51 (s, 3H), 1.25 (t,J = 7.4 Hz, 3H)

Example 024:2-ethyl-3-((5′-(2-methoxypyridin-3-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

A solution of Intermediate 001j (0.030 g, 0.041 mmol) and2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.029g, 0.123 mmol) in dioxane (3 mL) was treated with 2M aqueous K₃PO₄(0.103 mL, 0.205 mmol) and PdCl₂(dppf) (0.003 g, 4.11 mol) and reactedas described in Ex. 001. The crude residue was purified via preparativeHPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A:5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10mM NH₄OAc; Gradient: 15-55% B over 19 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min) to afford (0.0099 g, 0.019 mmol, 47%) of thetitle compound Example 024. LC-MS (Method A2): 0.77 min, [M+H]⁺=517.1;¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.20 (d, J=4.8 Hz, 1H), 7.87 (d, J=7.2Hz, 1H), 7.67 (s, 2H), 7.56 (s, 1H), 7.16-7.06 (m, 3H), 7.02 (d, J=8.0Hz, 2H), 6.95 (s, 1H), 5.44 (s, 2H), 3.89 (s, 3H), 2.77 (q, J=7.4 Hz,2H), 2.55 (s, 6H), 1.23 (t, J=7.4 Hz, 3H).

Example 025:3-((5′-(1H-pyrazol-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a vial charged with Intermediate 001j (0.030 g, 0.041 mmol),1H-pyrazole (0.0084 g, 0.123 mmol), copper(I) iodide (0.0039 g, 0.021mmol), potassium carbonate (0.028 g, 0.205 mmol) and L-proline (0.0047g, 0.041 mmol) was added DMSO (0.821 mL). The mixture was heated at 100°C. for 24 h and at 150° C. for an additional 24 h. The reaction mixturewas allowed to cool to RT and filtered through a microfilter. Theresidue was rinsed with DMSO and the filtrate purified via preparativeHPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A:5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10mM NH₄OAc; Gradient: 10-50% B over 20 minutes, then a 3-minute hold at100% B; Flow: 20 mL/min) to afford the title compound (Example 025,0.0051 g, 0.011 mmol, 27%). LC-MS (Method A2): 0.69 min, [M+H]⁺=476.1;¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.58 (d, J=2.1 Hz, 1H), 7.88 (dd, J=8.4,2.0 Hz, 1H), 7.82-7.73 (m, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.13 (d, J=7.9Hz, 2H), 7.01 (d, J=7.9 Hz, 2H), 6.95 (s, 1H), 6.55 (s, 1H), 5.45 (s,2H), 2.79 (q, J=7.3 Hz, 2H), 1.91 (s, 6H), 1.25 (t, J=7.5 Hz, 3H).

Example 026:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(4-fluorophenyl)-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-amine

Intermediate 026a:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(4-fluorophenyl)-6-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-amine

To a solution of Intermediate 001i (0.040 g, 0.060 mmol) in DCE (2 mL)containing 4A molecular sieves (previously heated at 110° C. undervacuum for 1 h prior to use) was added triethylamine (0.017 mL, 0.120mmol), pyridine (0.0097 mL, 0.120 mmol) and (4-fluorophenyl)boronic acid(0.025 g, 0.180 mmol). The reaction mixture was stirred for 15 min, thencopper (II) acetate (0.011 mg, 0.060 mmol) was added. The reaction vialwas sealed under an air atmosphere and allowed to stir at RT overnight.After 16 h, the reaction mixture was filtered over Celite, washed withDCM and concentrated to afford a green residue (Intermediate 026a) whichwas used as such in the next step. LC-MS (Method A2): 1.07 min,[M+H]⁺=761.5.

Example 026:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(4-fluorophenyl)-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-amine

A solution of Intermediate 026a (0.040 g, 0.053 mmol) in DCM (2 mL) wastreated with triethylsilane (0.084 mL, 0.526 mmol) followed by TFA(0.203 mL, 2.63 mmol). The reaction was stirred at RT for 10 min, thenconcentrated to dryness. The residue was taken up in DMF, the mixturewas neutralized with a few drops of triethylamine, filtered and purifiedvia preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 20-60% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min). A further purification bypreparative LC-MS was performed on the resulting sample (Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 0.1%TFA; Mobile Phase B: 95:5 ACN: H₂O with 0.1% TFA; Gradient: 20-60% Bover 20 minutes, then a 3-minute hold at 100% B; Flow: 20 mL/min) toafford the title compound (Example 026, 0.0021 g, 0.004 mmol, 8%). LC-MS(Method A2): 0.78 min, [M+H]⁺=519.1; ¹H NMR (500 MHz, DMSO-d₆) δ ppm7.94 (s, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.23-7.00 (m, 9H), 6.95 (d, J=1.8Hz, 1H), 5.55 (s, 2H), 2.96-2.90 (m, 2H), 2.51 (br s, 6H), 1.21 (t,J=7.5 Hz, 3H).

Example 027:2-(4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)isoindoline-1,3-dione

Intermediate 027a4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-amine

To a solution of Intermediate 001 g (0.270 g, 0.594 mmol) in MeOH (30mL) was added zinc powder (0.777 g, 11.88 mmol) followed by ammoniumchloride (0.953 g, 17.82 mmol) and the mixture was heated at reflux at70° C. overnight. Then the reaction mixture was partially concentratedunder reduced pressure and the residue was partitioned between EtOAc (30mL) and saturated aqueous NH₄Cl (30 mL). The corresponding mixture wasstirred vigorously for 2 h and filtered. The filtrate was furtherdiluted with EtOAc and the aqueous phase was separated and againextracted with EtOAc (2×). The combined organic phase was dried overMgSO₄, filtered and concentrated to afford the title compound(Intermediate 027a, 0.148 g, 0.349 mmol, 59%). LC-MS (Method A2): 0.59min, [M+H]⁺=425.3; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.26 (d, J=8.3 Hz,1H), 7.03-6.92 (m, 5H), 6.66 (d, J=8.3 Hz, 1H), 6.59 (s, 1H), 5.43 (s,2H), 2.74 (q, J=7.3 Hz, 2H), 2.55 (s, 6H), 1.18 (t, J=7.5 Hz, 3H).

Example 027:2-(4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)isoindoline-1,3-dione

A solution of Intermediate 027a (0.010 g, 0.024 mmol) in AcOH (0.5 mL)was treated with phthalic anhydride (0.035 g, 0.236 mmol). The reactionvial was sealed and heated at/at 100° C. for 16 h. The mixture wasconcentrated, dissolved in DMF, filtered and purified via preparativeHPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A:5:95 ACN: H₂O with 0.1% TFA; Mobile Phase B: 95:5 ACN: H₂O with 0.1%TFA; Gradient: 15-55% B over 20 minutes, then a 5-minute hold at 100% B;Flow: 20 mL/min) to afford the title compound (Example 027, 0.0081 g,0.015 mmol, 62%). LC-MS (Method A2): 0.74 min, [M+H]⁺=555.4; ¹H NMR (500MHz, DMSO-d₆) δ ppm 7.98 (br. s., 2H), 7.94 (br s, 2H), 7.82 (d, J=8.1Hz, 1H), 7.71-7.62 (m, 2H), 7.18-7.05 (m, 5H), 5.55 (s, 2H), 2.90 (q,J=7.4 Hz, 2H), 2.54 (br s, 6H), 1.21 (t, J=7.4 Hz, 3H).

Example 028:1-(4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)pyrrolidin-2-one

A suspension of Intermediate 027a (0.009 g, 0.021 mmol) in DMF (1 mL)was treated with 4-chlorobutanoyl chloride (7.13 μL, 0.064 mmol) and NaH(0.0025 g, 0.064 mmol). The corresponding reaction mixture was allowedto stir at RT overnight. The reaction was quenched with a few drops ofH₂O, filtered and purified via preparative HPLC (Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mMNH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient:10-50% B over 19 minutes, then a 5-minute hold at 100% B; Flow: 20mL/min). The material was further purified via a second preparativeLC-MS (Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A:5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10mM NH₄OAc; Gradient: 10-50% B over 19 minutes, then a 5-minute hold at100% B; Flow: 20 mL/min) to afford the title compound (Example 028,0.008 g, 0.020 mmol, 95%). LC-MS (Method A2): 0.66 min, [M+H]⁺=493.3; ¹HNMR (500 MHz, DMSO-d₆) δ ppm 7.65-7.60 (m, 1H), 7.59-7.51 (m, 2H), 7.07(d, J=8.1 Hz, 2H), 6.95 (d, J=9.2 Hz, 3H), 5.42 (s, 2H), 3.88 (t, J=6.9Hz, 2H), 2.79 (q, J=7.5 Hz, 2H), 2.52-2.48 (m, 8H), 2.12-2.00 (m, 2H),1.26 (t, J=7.4 Hz, 3H).

Example 029:2-Ethyl-3-((5′-(6-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a vial containing (Intermediate 001j (0.030 g, 0.041 mmol), Pd(Ph₃P)₄ (4.74 mg, 4.11 mol) and 2-methoxy-6-(tributylstannyl)pyridine(0.033 g, 0.082 mmol) was added toluene (1 mL). The mixture was spargedwith N₂ for 2 min before the reaction vessel was sealed and heated at110° C. for 3 h. The reaction mixture was cooled to RT and concentrated.The crude residue was taken up in DCM (1 mL) and treated withtriethylsilane (0.033 mL, 0.205 mmol) followed by TFA (0.127 mL, 1.642mmol). The resulting reaction mixture was stirred for 10 min beforebeing concentrated, taken up in DMF and purified via preparative HPLCwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile PhaseB: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 15-57% B over 20 minutes,then a 3-minute hold at 100% B; Flow: 20 mL/min. Fractions containingthe desired product were combined and dried via centrifugal evaporationto afford the title compound (Example 029, 0.008 g, 0.015 mmol, 36%).LC-MS (Method A2): 0.83 min, [M+H]⁺=517.0; ¹H NMR (600 MHz, DMSO-d₆) δppm 8.13 (dd, J=8.1, 1.8 Hz, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.78 (t, J=7.9Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.13 (d, J=7.9Hz, 2H), 7.01 (d, J=8.1 Hz, 2H), 6.95 (s, 1H), 6.80 (d, J=8.1 Hz, 1H),5.45 (s, 2H), 3.93 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 2.55 (s, 9H), 1.25(t, J=7.5 Hz, 3H).

Example 030:2-Ethyl-5,7-dimethyl-3-((5′-(pyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

A mixture of Intermediate 001j (0.030 g, 0.041 mmol), Pd (Ph₃P)₄ (0.005mg, 4.11 mol), 2-(tributylstannyl)pyridine (0.030 g, 0.082 mmol) andtoluene (1 mL) was treated as described in Example 29. After cooling atRT, the reaction mixture was concentrated, retaken in DCM (1 mL) andtreated with triethylsilane (0.033 mL, 0.205 mmol) followed by TFA(0.127 mL, 1.642 mmol) for 20 min. Then the reaction mixture wasconcentrated, the crude was taken up in DMF and purified via preparativeLC-MS with the following conditions: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; MobilePhase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 10-52% B over 20minutes, then a 3-minute hold at 100% B; Flow: 20 mL/min Fractionscontaining the desired product were combined and dried via centrifugalevaporation to afford the title compound Example 030 (0.014 g, 0.027mmol, 67%). LC-MS (Method A2): 0.64 min, [M+H]⁺=487.0; ¹H NMR (600 MHz,DMSO-d₆) δ ppm 8.68 (d, J=4.0 Hz, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.13-8.03(m, 2H), 7.90 (t, J=7.6 Hz, 1H), 7.75 (br. s., 1H), 7.40 (dd, J=7.2, 4.9Hz, 1H), 7.12 (br. s., 2H), 7.03 (d, J=6.3 Hz, 2H), 6.95 (s, 1H), 5.45(s, 2H), 2.77 (q, J=7.3 Hz, 2H), 2.55 (s, 6H), 1.23 (t, J=7.4 Hz, 3H).

Example 031:4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylicacid

A solution of Intermediate 001d (0.035 g, 0.089 mmol) and3-chloro-[1,1′-biphenyl]-4-carboxylic acid (0.031 g, 0.134 mmol) indioxane (2.5 mL) was was treated with 2M aqueous K₃PO₄ (0.224 mL, 0.447mmol) followed by PdCl₂(dppf) (0.0065 g, 8.94 μmol) as described inExample 001. LC-MS showed only traces of the desired compound. MorePdCl₂(dppf) was added (0.0065 g, 8.94 μmol) and the reaction mixture washeated at 100° C. overnight. The reaction mixture was cooled to RT,filtered over a pad of Celite/MgSO₄ and concentrated. The resultingresidue was dissolved in DMF, filtered and purified via preparativeLC-MS with the following conditions: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; MobilePhase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 15-55% B over 20minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min Fractionscontaining the desired product were combined and dried via centrifugalevaporation. to afford the title compound Example 031 (0.005 g, 0.011mmol, 12%). LC-MS (Method A2): 0.87 min, [M+H]⁺=462.0. ¹H NMR (400 MHz,DMSO-d₆) δ 7.81-7.66 (m, 4H), 7.56 (s, 1H), 7.51-7.44 (m, 2H), 7.43-7.36(m, 3H), 7.16 (d, J=8.1 Hz, 2H), 6.96 (s, 1H), 5.51 (s, 2H), 2.83 (q,J=7.5 Hz, 2H), 2.53 (s, 6H), 1.27 (t, J=7.5 Hz, 3H).

Example 032:3-(4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-1,2,4-oxadiazol-5(4H)-one

Intermediate 032a: 3-bromo-[1,1′-biphenyl]-4-carbonitrile

To a vial charged with [1,1′-biphenyl]-4-carbonitrile (500 mg, 2.79mmol), NBS (447 mg, 2.51 mmol) (recrystallized), CSA (324 mg, 1.395mmol) and diacetoxypalladium (62.6 mg, 0.279 mmol) was added DCE (11.2mL). The reaction mixture was sealed and heated at 80° C. for 15 h (J.Org. Chem, 2013, 78, 2786). The reaction mixture was diluted with EtOAcand concentrated directly onto Celite® for ISCO purification (0-50%EtOAc/Hex) to afford the title compound Intermediate 032a (400 mg, 1.550mmol, 55.5% yield) as a white solid. LC-MS (Method A2): 1.07 min, [M+H]No ion observed; ¹H NMR (400 MHz, DMSO-d₆) 8.20 (d, J=1.6 Hz, 1H), 8.027(d, J=8 Hz, 1H), 7.92-7.89 (m, 1H), 7.81-7.79 (m, 2H), 7.55-7.48 (m,3H).

Intermediate 032b:4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

To a solution of Intermediate 001d (150 mg, 0.383 mmol) and I-003A (189mg, 0.498 mmol) in dioxane (3 mL) was added K₃PO₄ (2 M, aq) (0.575 mL,1.150 mmol) followed by PdCl₂(dppf) (28.0 mg, 0.038 mmol). The resultingmixture was sparged with N₂ for 2 min before the vessel was sealed andheated at 120° C. for 45 min in the microwave. The crude reaction wasdiluted with EtOAc and filtered through celite. The filtrate wasconcentrated and the residue was dissolved in a small amount ofmethylene chloride and charged to a 40 g silica gel cartridge which waseluted with a 30 min gradient of of 0-100% EtOAc in hexane to afford thetitle compound (Intermediate 032b, 133 mg, 0.301 mmol, 78% yield), as awhite solid. LC-MS (Method A2): 0.92 min, [M+H]⁺=443.1; ¹H NMR (500 MHz,CDCl₃) δ 7.83 (d, J=8.0 Hz, 1H), 7.70-7.65 (m, 2H), 7.64-7.61 (m, 2H),7.56 (d, J=8.3 Hz, 2H), 7.53-7.47 (m, 2H), 7.47-7.42 (m, 1H), 7.31-7.26(m, 3H), 6.94 (s, 1H), 5.56 (s, 2H), 2.90-2.83 (m, 2H), 2.67 (s, 3H),2.63 (s, 3H), 1.37 (t, J=7.6 Hz, 3H).

Example 032:3-(4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-1,2,4-oxadiazol-5(4H)-one

Hydroxylamine hydrochloride (70.7 mg, 1.017 mmol) was dissolved in DMSO(1 mL). TEA (0.142 mL, 1.017 mmol) was added and the reaction wasallowed to stir at RT for 5 minutes. The mixture was then diluted withTHF (1 mL) and filtered. The THF was then concentrated from the filtrateunder reduced pressure and the resulting DMSO solution was added to asolution of Intermediate 032b (15 mg, 0.034 mmol) in 0.5 mL of DMSO. Themixture was heated at 80° C. for 15 hours. The reaction was diluted with4 mL of H₂O and the precipitate was filtered off. This precipitate wasredissolved in DMF (2 mL) and DBU (0.026 mL, 0.169 mmol) was added. CDI(55.0 mg, 0.339 mmol) was then added and the reaction mixture wasallowed to stir at RT for 10 minutes before being filtered and purifiedby preparative LC-MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mMNH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient:20-60% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20mL/min Fractions containing the desired product were combined and driedvia centrifugal evaporation to afford the title compound (Example 032,1.9 mg, 0.004 mmol, 11% yield). LC-MS (Method A2): 0.84 min,[M+H]⁺=502.1; ¹H NMR (500 MHz, CDCl₃) δ 7.80-7.71 (m, 1H), 7.69-7.58 (m,1H), 7.51-7.44 (m, 1H), 7.42-7.37 (m, 1H), 7.34 (d, J=7.6 Hz, 2H), 7.13(d, J=7.9 Hz, 2H), 6.96 (s, 1H), 5.49 (s, 2H), 2.80 (q, J=7.4 Hz, 2H),2.55 (s, 6H), 1.23 (t, J=7.5 Hz, 3H).

Example 033:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 033a:2-butyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one

A suspension of 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one, HCl (0.150 g,0.650 mmol) and2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.232g, 0.780 mmol) in DMF (3.25 mL) was treated with potassium carbonate(0.270 g, 1.950 mmol) according to the procedure described in Synth.Commun., 2005, 35, 1979. After 20 h of stirring, the reaction mixturewas diluted with EtOAc and filtered over Celite®. The organic phase waswashed with brine, dried over MgSO₄, re-filtered over Celite®,concentrated and purified by ISCO (EtOAc/Hexanes, 0-100%) to afford thetitle compound (Intermediate 033a, 0.200 g, 0.487 mmol, 75.0% yield) asa viscous oil. LC-MS (Method A2): 0.89 min, [M+H]⁺=411.2; ¹H NMR (400MHz, CDCl₃) δ ppm 7.77 (d, J=8.1 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H), 4.68(s, 2H), 2.29-2.21 (m, 2H), 2.03-1.87 (m, 6H), 1.86-1.74 (m, 2H),1.59-1.49 (m, 2H), 1.38-1.21 (m, 14H), 0.85 (t, J=7.4 Hz, 3H).

Intermediate 033b:4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

To a solution of Intermediate 033a (0.050 g, 0.122 mmol) andIntermediate 032a (0.047 g, 0.183 mmol) in dioxane (3 mL) was addedK₃PO₄ (2 M, aq., 0.183 mL, 0.366 mmol) followed by PdCl₂(dppf) (0.009 g,0.012 mmol). The resulting mixture was sparged with N₂ for 2 min beforethe vessel was sealed and heated at 120° C. for 45 min under microwaveirradiation. The reaction mixture was cooled to RT, diluted with EtOAcand filtered over a pad of Celite®/MgSO₄. The filtrate was concentratedto a brown residue which was purified by ISCO (EtOAc/Hexanes, 0-100%) toafford the title compound (Intermediate 033b, 0.053 g, 0.115 mmol, 94%yield) as a viscous oil. LC-MS (Method A2): 0.96 min, [M+H]⁺=462.2; ¹HNMR (400 MHz, CDCl₃) δ ppm 7.83 (d, J=7.9 Hz, 1H), 7.71-7.64 (m, 2H),7.64-7.57 (m, 4H), 7.53-7.40 (m, 3H), 7.30 (d, J=8.1 Hz, 2H), 4.76 (s,2H), 2.39-2.33 (m, 2H), 2.04-1.90 (m, 6H), 1.90-1.80 (m, 2H), 1.61 (dt,J=15.5, 7.6 Hz, 2H), 1.42-1.30 (m, 2H), 0.88 (t, J=7.4 Hz, 3H).

Example 033:3-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

A vial containing Intermediate 033b (0.053 g, 0.115 mmol) and dibutyltinoxide (0.057 g, 0.230 mmol) in toluene (1.15 mL) was treated with TMS-N₃(0.152 mL, 1.148 mmol) according to the procedure described forIntermediate 001 g. After cooling, the reaction mixture was diluted withMeOH and EtOAc and quenched by the portionwise addition of a 10% aqueoussolution of CAN (6.30 g, 1.148 mmol) until bubbling ceased. Then theorganic phase was washed with saturated aqueous NH₄Cl and brine, driedover MgSO₄, filtered over Celite® and concentrated. The crude residuewas taken up in DMF, filtered and purified via preparative LC-MS(Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mMNH₄OAc; Gradient: 10-100% B over 25 minutes, then a 10-minute hold at100% B; Flow: 20 mL/min) to afford 0.0055 g (0.011 mmol, 10%) of thetitle compound Example 033. LC-MS (Method A2): 0.85 min, [M+H]⁺=505.1;¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.88-7.78 (m, 3H), 7.77-7.70 (m, 2H),7.55-7.47 (m, 2H), 7.46-7.39 (m, 1H), 7.19 (d, J=7.7 Hz, 2H), 7.09 (d,J=7.8 Hz, 2H), 4.69 (s, 2H), 2.31 (t, J=7.5 Hz, 2H), 1.92-1.76 (m, 6H),1.67 (d, J=6.6 Hz, 2H), 1.48 (quint, J=7.4 Hz, 2H), 1.27 (sext, J=7.4Hz, 2H), 0.81 (t, J=7.3 Hz, 3H).

Example 034:(S)-2-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid

Intermediate 034a: (S)-Methyl3-methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)butanoate

To a suspension containing (S)-methyl 2-amino-3-methylbutanoate, HCl(0.169 g, 1.010 mmol) and2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.250g, 0.842 mmol) in ACN (2.81 mL) was added potassium carbonate (0.465 g,3.37 mmol). The reaction vessel was sealed and the mixture was heated at70° C. for 5 h. The cooled reaction mixture was diluted with EtOAc andfiltered over Celite®. The resulting mixture was concentrated to affordthe crude product, which was used as such in the next step. LC-MS(Method A2): 0.75 min, [M+H]⁺=348.1.

Intermediate 034b: (S)-Methyl3-methyl-2-(N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pentanamido)butanoate

To a solution of crude Intermediate 034a (0.250 g, 0.720 mmol) in DCM(7.2 mL) was added Hünig's base (0.63 mL, 3.60 mmol) followed by valerylchloride (0.17 mL, 1.440 mmol). After 15 min of stirring, the reactionmixture was concentrated and purified by ISCO (EtOAc/Hexanes, 0-50%) toafford the title compound (Intermediate 034b, 0.250 g, 0.406 mmol, 56.4%yield) as a yellow oil. LC-MS (Method A2): 1.18 min, [M+H]⁺=432.2; ¹HNMR (400 MHz, CDCl₃) δ ppm 7.75 (d, J=7.9 Hz, 2H), 7.14 (d, J=7.9 Hz,2H), 4.98 (d, J=10.6 Hz, 1H), 4.63 (s, 2H), 3.44 (s, 3H), 2.32-2.23 (m,2H), 2.21-2.12 (m, 1H), 1.67-1.52 (m, 2H), 1.35-1.31 (m, 12H), 1.29-1.15(m, 2H), 1.00-0.93 (m, 3H), 0.88 (d, J=6.8 Hz, 3H), 0.86-0.77 (m, 3H).

Intermediate 034c: (S)-Methyl2-(N-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate

To a solution of Intermediate 034b (0.060 g, 0.139 mmol) andIntermediate 032a (0.054 g, 0.209 mmol) in dioxane (3 mL) was addedK₃PO₄ (2M aq, 0.209 mL, 0.417 mmol) followed by PdCl₂(dppf) (0.011 g,0.014 mmol) and the resulting mixture was reacted as described inExample 033b. The cooled reaction mixture was diluted with EtOAc andfiltered over a pad of Celite®/MgSO₄. The filtrate was concentrated to abrown residue which was purified by ISCO (EtOAc/Hexanes, 0-100%) toafford the title compound (Intermediate 034c, 0.064 g, 0.080 mmol,57.2%) as a yellow oil. LC-MS (Method A2): 1.21 min, [M+H]⁺=483.1; ¹HNMR (400 MHz, CDCl₃) δ ppm 7.85-7.78 (m, 1H), 7.72-7.66 (m, 1H),7.65-7.56 (m, 4H), 7.54-7.39 (m, 4H), 7.36-7.28 (m, 2H), 4.97 (d, J=10.3Hz, 1H), 4.70 (s, 2H), 3.47 (s, 3H), 2.53-2.34 (m, 3H), 1.70-1.56 (m,2H), 1.36-1.28 (m, 2H), 1.00 (d, J=6.6 Hz, 6H), 0.93-0.89 (m, 3H).

Intermediate 034d: (S)-Methyl2-(N-((6′-(1H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate

To a vial containing Intermediate 034c (0.060 g, 0.124 mmol) was addeddibutyltin oxide (0.031 g, 0.124 mmol) and toluene (2 mL) followed byTMS-N₃ (0.083 mL, 0.622 mmol). The reaction vial was sealed and themixture heated at 100° C. overnight. After 14 h of heating, LC-MS showed70% conversion to the desired tetrazole. Another aliquot of TMS-N₃(0.083 mL, 0.622 mmol) was added and heating was continued for another 6h. The cooled reaction mixture was then diluted with EtOAc and a smallamount of MeOH was added to fully solubilize the tetrazole product. Tothis organic phase was added CAN (10% aqueous) (6.82 g, 1.244 mmol) andthe residue was vigorously stirred until bubbling ceased. The organicphase was separated, concentrated and used as such in the next step(quantitative yield of Intermediate 034d was assumed). LC-MS (MethodA2): 1.07 min, [M+H]⁺=526.1.

Example 034:(S)-2-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid To a solution of crude Intermediate034d (0.050 g, 0.095 mmol) in THF (1 mL) was added H₂O (1 mL) followedby LiOH monohydrate (0.040 g, 0.951 mmol). The resulting emulsion wassonicated and vigorously stirred for 20 min before being heated at 65°C. overnight. After cooling to RT, the mixture was diluted with EtOAcand washed with 1 M HCl. The cloudy organic phase was concentrated to acrude yellow oil, which was taken up in DMF, filtered and purified viapreparative LC-MS (Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 15-55% B over 19 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min) to afford 0.012 g (0.024 mmol,25%) of the title compound Example 034. LC-MS (Method A2): 1.01 min,[M+H]⁺=512.1; ¹H NMR (500 MHz, DMSO-d₆ at 100° C.) δ ppm 7.79-7.67 (m,4H), 7.62-7.58 (m, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.43-7.36 (m, J=7.7 Hz,1H), 7.26-7.11 (m, 4H), 4.70-4.47 (m, 2H), 3.58-3.50 (m, 1H), 2.40-2.15(m, 3H), 1.61-1.43 (m, 2H), 1.36-1.21 (m, 2H), 0.98 (d, J=6.3 Hz, 3H),0.81 (d, J=6.9 Hz, 6H). [Note: VT NMR used to coalesce rotomer peaks].

Example 035:(1-((6′-(1H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methanol

Intermediate 035a:2-Butyl-4-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carbaldehyde

A solution of 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde (300 mg,1.607 mmol) and 4-(bromomethyl)benzenboronic acid pinacol ester (501 mg,1.688 mmol) in N,N-dimethylacetamide (5358 μl) was cooled to −10° C. Tothis cooled solution was added potassium carbonate (244 mg, 1.768 mmol)(9:15 am) and the mixture was stirred vigorously for 1 h before beingallowed to warm to RT and stir for an additional 3 h. The crude reactionmixture was filtered over Celite® and rinsed with a 3 mL of DMA. Thissolution containing the title compound (Intermediate 035a) was takendirectly into the subsequent sodium borohydride reduction withoutfurther purification. LC-MS (Method A2): 1.19 min, [M+H]⁺=403.1, 405.1.

Intermediate 035b:(2-Butyl-4-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazol-5-yl)methanol

To the crude solution of Intermediate 035a (483 mg, 1.200 mmol) in DMA(9 mL) was added MeOH (9 mL) followed by sodium borohydride (113 mg,3.00 mmol). After 2 h of stirring, 2 mL of AcOH was added to quench thereaction, and the resulting reaction mixture was concentrated to a cruderesidue. This residue was purified by ISCO (0-100% EtOAc/Hex) to affordthe title compound (Intermediate 035b, 380 mg, 0.939 mmol, 78% yieldover the two-step process) as an amorphous white solid. LC-MS (MethodA2): 0.91 min, [M+H]⁺=405.1, 407.1. ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d,J=8.1 Hz, 2H), 6.98 (d, J=8.1 Hz, 2H), 5.23 (s, 2H), 4.46 (s, 2H),2.57-2.50 (m, 2H), 1.70-1.57 (m, 2H), 1.38-1.29 (m, 14H), 0.86 (t, J=7.4Hz, 3H).

Intermediate 035c:4″-((2-Butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

To a solution of Intermediate 035b (90 mg, 0.222 mmol) and Intermediate032a (86 mg, 0.334 mmol) in dioxane (3 mL) was added K₃PO₄ (2 M, aq)(0.222 mL, 0.445 mmol) followed by PdCl₂(dppf) (16.27 mg, 0.022 mmol).The resulting mixture was sparged with N₂ for 2 min before being sealedand heated at 120° C. for 45 min in the microwave. The reaction mixturewas cooled to RT, diluted with EtOAc and filtered over a pad ofCelite®/MgSO₄. The filtrate was concentrated to a brown residue whichwas purified by ISCO (0-100% EtOAc/Hex) to afford the title compound(Intermediate 035c, 65 mg, 0.143 mmol, 64.1% yield) as a light brownoil. LC-MS (Method A2): 0.97 min, [M+H]⁺=456.0, 458.0. ¹H NMR (400 MHz,CDCl₃) δ 7.85-7.80 (m, 1H), 7.70-7.65 (m, 2H), 7.64-7.56 (m, 4H),7.53-7.42 (m, 3H), 7.14 (d, J=8.4 Hz, 2H), 5.30 (s, 2H), 4.54 (d, J=5.3Hz, 2H), 2.65-2.57 (m, 2H), 1.75-1.64 (m, 2H), 1.43-1.31 (m, 2H), 0.89(t, J=7.3 Hz, 3H).

Example 035:(1-((6′-(1H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazol-5-yl)methanol

To a vial containing Intermediate 035c (65 mg, 0.143 mmol) was addeddibutyltin oxide (35.5 mg, 0.143 mmol) and toluene (1.5 mL) followed byTMS-N₃ (0.095 mL, 0.713 mmol). The reaction mixture was sealed andheated at 100° C. behind a blast shield. After 16 h of heating, thereaction mixture was diluted with EtOAc and a small amount of MeOH wasadded to fully solubilize the tetrazole product. To this organic phasewas added CAN (10% aqueous) and the residue was vigorously stirred untilbubbling ceased. The organic phase was separated, concentrated, retakenin DMF, filtered and purified via preparative LC-MS with the followingconditions: Column: XBridge Phenyl, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂Owith 10 mM NH₄OAc; Gradient: 20-60% B over 19 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min Fractions containing the desired productwere combined and dried via centrifugal evaporation to afford the titlecompound (Example 035, 0.001 g, 0.001 mmol, 1%). LC-MS (Method A2): 0.87min, [M+H]⁺=499.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.74 (d, J=7.6 Hz, 1H),7.68 (br. s., 1H), 7.54 (s, 1H), 7.47 (t, J=7.5 Hz, 2H), 7.41-7.34 (m,1H), 7.19 (br. s., 2H), 6.94 (d, J=7.3 Hz, 2H), 5.23 (s, 2H), 4.32 (s.,2H), 2.51-2.45 (m, 2H), 1.49 (quin, J=7.4 Hz, 2H), 1.32-1.21 (m, 2H),0.82 (t, J=7.3 Hz, 3H).

Example 039: Butyl(3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(o-tolyl)thiophen-2-yl)sulfonylcarbamate

Intermediate 039a:3-((6-Bromopyridin-3-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001c (0.491 g, 2.800 mmol) in NMP (15 mL)was added freshly pulverized NaOH (0.230 g, 5.74 mmol). The resultingmixture was stirred at RT under N₂ for 1 h and then it was cooled at 0°C. and a solution of 2-bromo-5-(bromomethyl)pyridine (0.738 g, 2.94mmol) in NMP (3 mL) was added over 5 min. The cooling bath wassubsequently removed and the reaction mixture was stirred at RT for 48h. The resulting mixture was cooled at 0° C. and H₂O (40 mL) was addeddropwise over ca. 15 min. The cooling bath was then removed and theresulting solution was stirred at RT for several hours. The resultinghomogenous mixture was extracted with EtOAc (×2) and the combinedorganic phase was washed with brine, dried (Na₂SO₄) and evaporated togive an amber solid which was purified by ISCO (0-100%, EtOAc-DCM) toafford the pure product as a white solid (Intermediate 039a, 0.757 g,78%). LC (Method B): 1.586 min; HRMS (ESI): Calcd. for C₁₆H₁₈BrN₄ [M+H]⁺m/z 345.0719; found 345.0715; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.33 (d,J=2.35 Hz, 1H), 7.57 (d, J=8.22 Hz, 1H), 7.44 (dd, J=8.22, 2.35 Hz, 1H),6.94 (s, 1H), 5.45 (s, 2H), 2.81 (q, J=7.43 Hz, 2H), 2.50 (s, 6H underDMSO), 1.22 (t, J=7.43 Hz, 3H).

Intermediate 039b: N-(tert-Butyl)-5-(o-tolyl)thiophene-2-sulfonamide

A mixture of 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (0.596 g,2.000 mmol) and o-tolylboronic acid (0.408 g, 3.00 mmol) intoluene-ethanol (9:1, 10 mL) was purged with a stream of N₂ for 20 minin a sealable vial. To this mixture was added Pd (Ph₃P)₄ (0.231 g, 0.200mmol) and 2 M aqueous Na₂CO₃ (3.00 mL, 6.00 mmol), the vial was sealedand the mixture was stirred at 95° C. overnight. The cooled mixture wasfiltered and the residue was washed with EtOAc. The filtrate was washed(sat. aq. NaHCO₃), dried (Na₂SO₄) and evaporated to give a dark browngum. This material was purified by ISCO (0-50%, EtOAc-hexane) to givethe title compound (Intermediate 039b, 0.490 g, 79% yield) as a whitesolid. LC (Method B): 2.124 min; HRMS (ESI): Calcd. for C₁₅H₂₀NO₂S₂[M+H]⁺ m/z 310.0935; found: 310.0923; ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.76 (s, 1H), 7.56 (d, J=3.91 Hz, 1H), 7.40 (d, J=7.83 Hz, 1H),7.32-7.36 (m, 2H), 7.28 (d, J=7.43 Hz, 1H), 7.18 (d, J=3.91 Hz, 1H),2.37 (s, 3H), 1.18 (s, 9H).

Intermediate 039c:(2-(N-(tert-Butyl)sulfamoyl)-5-(o-tolyl)thiophen-3-yl)boronic acid

A solution of Intermediate 039b (0.409 g, 1.322 mmol) in dry THF (15 mL)was cooled at −78° C. under N₂ and a solution of 1.6 M n-BuLi in hexanes(2.065 mL, 3.30 mmol) was added dropwise over 5 min. The mixture wasstirred for 30 min and then the temperature was raised to about −20° C.(−10° C. to −18° C. using ice-MeOH) and stirring was continued at thattemperature for 3 h. The resulting light yellow solution was recooled at−78° C. and triisopropyl borate (0.460 mL, 1.983 mmol) was addeddropwise. Stirring was continued as the cooling bath dischargedovernight. The resulting turbid mixture was quenched with 2M HCl (9.91mL, 19.83 mmol) and the mixture was stirred for 30 min. This mixture wasthen partitioned with EtOAc-H₂O and the organic phase was separated,washed (H₂O, brine), dried (Na₂SO₄) and evaporated to give a gum. Thisgum was purified by flash chromatography (ISCO 0-100%, EtOAc-hex) toafford the title compound (Intermediate 039c, 0.192 g, 41%). LC-MS(APCI): Calcd. for C₁₅H₁₉BNO₄S₂ [M−H]⁻ m/z 352.0849; found: 352.2; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.60 (s, 1H), 7.39 (d, J=7.83 Hz, 1H),7.23-7.33 (m, 4H), 2.38 (s, 3H), 1.18 (s, 9H).

Intermediate 039d:N-(tert-Butyl)-3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(o-tolyl)thiophene-2-sulfonamide

A mixture of Intermediate 039a (0.086 g, 0.250 mmol), Intermediate 039c(0.132 g, 0.375 mmol), 2 M aqueous Na₂CO₃ (0.50 mL, 1.00 mmol) and Pd(Ph₃P)₄ (0.029 g, 0.025 mmol) in toluene-ethanol (9:1, 10 mL) wastreated as described in Example 039b. The cooled mixture was dilutedwith EtOAc and the organic phase was separated, dried (Na₂SO₄) andevaporated to give an amber gum. This material was taken up in DMF andpurified by preparative LC (Method C) to give the title compound(Intermediate 039d, 0.163 g, 81% yield) as a colourless gum which wasused as such in the next step. LC (Method B): 2.169 min; HRMS (ESI):Calcd. for C₃₁H₃₆N₅O₂S₂ [M+H]⁺ m/z 574.2310; found: 574.2332; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.71 (s, 1H), 7.84-7.93 (m, 2H), 7.68 (d,J=7.83 Hz, 1H), 7.59 (s, 1H), 7.47 (d, J=7.43 Hz, 1H), 7.34 (dd, J=3.72,2.15 Hz, 2H), 7.24-7.32 (m, 1H), 7.08 (br s, 1H), 5.62 (br s, 2H), 2.97(d, J=7.04 Hz, 2H), 2.53 (d, J=2.74 Hz, 6H), 2.40 (s, 3H), 1.28 (t,J=7.43 Hz, 3H), 1.13 (s, 9H).

Intermediate 039e:3-(5-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(o-tolyl)thiophene-2-sulfonamide

To a mixture of Intermediate 039d (0.144 g, 0.180 mmol) in DCM (3 mL)and anisole (0.196 mL, 1.796 mmol) was added TFA (5 mL) and the mixturewas stirred at RT in a sealed flask overnight. The volatiles wereremoved under reduced pressure and the residue was evaporated from ACNsolution (×2) to give a colourless gum. Quantitative yield ofIntermediate 039e was assumed and this material was used as such in thenext step without further purification. LC-MS (APCI): Calcd. forC₂₇H₂₈N₅O₂S₂ [M+H]⁺ m/z 518.1684; found: 518.1.

Example 039: Butyl(3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(o-tolyl)thiophen-2-yl)sulfonylcarbamate

A solution of Intermediate 039e (0.045 g, 0.060 mmol) in pyridine (1 mL)was treated with triethylamine (0.063 mL, 0.450 mmol),4-(pyrrolidin-1-yl)pyridine (0.027 g, 0.180 mmol) and butylcarbonochloridate (0.024 mL, 0.180 mmol) and the reaction mixture wasstirred at RT overnight. The reaction mixture was subsequentlyevaporated to dryness to give a solid residue. The residue was taken upin DMF, the mixture was acidified with AcOH and the solution wassubmitted to preparative LC purification (Method D) to give the titlecompound (Example 039, 0.023 g, 0.037 mmol, 62% yield) as a white solid.LC (Method B): 2.125 min; HRMS (ESI): Calcd. for C₃₂H₃₆N₅O₄S₂ [M+H]⁺ m/z618.2209; found 618.2224; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.52-8.56 (m,1H), 7.83 (d, J=7.83 Hz, 1H), 7.65 (dd, J=8.41, 2.15 Hz, 1H), 7.56 (s,1H), 7.47 (d, J=7.43 Hz, 1H), 7.34-7.38 (m, 2H), 7.27-7.33 (m, 1H), 6.98(s, 1H), 5.56 (s, 2H), 3.96 (t, J=6.46 Hz, 2H), 2.85 (q, J=7.43 Hz, 2H),2.51-2.52 (m, 6H), 2.39-2.44, (m, 3H), 1.36-1.45 (m, 2H), 1.26 (t,J=7.43 Hz, 3H), 1.15-1.20 (m, 3H), 0.76 (t, J=7.43 Hz, 3H).

Example 040: Butyl(3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(o-tolyl)thiophen-2-yl)sulfonylcarbamate

Intermediate 040a:3-(4-Bromobenzyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

A solution of Intermediate 001c (0.491 g, 2.800 mmol) in NMP (10 mL) wastreated with a solution of NaOH (0.230 g, 5.74 mmol) in NMP (2 mL)followed with a solution of 1-bromo-4-(bromomethyl)benzene (0.735 g,2.94 mmol) in NMP (2 mL) as described in Example 039a. The cooling bathwas then removed and the reaction mixture was stirred at RT for 1.5 h.The mixture was cooled at 0° C. and H₂O (40 mL) was added dropwise overca.15 min. The cooling bath was then removed and the resulting slurrywas stirred at RT for 1 h. The mixture was then filtered and the filtercake was washed with NMP-H₂O (1:3, 10 mL) and then H₂O (2×20 mL). Theresulting solid was dried in vacuo in a dessicator to give the titlecompound (Intermediate 040a, 0.637 g, 66.1% yield) as a beige solid.This material was used as such in the next step. LC (Method B): 1.815min; HRMS (ESI): Calcd. for C₁₇H₁₉BrN₃ [M+H]⁺ m/z 344.0762; found344.0756; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.47-7.53 (m, 2H), 7.02-7.08(m, 2H), 6.93 (s, 1H), 5.41 (s, 2H), 2.74 (q, J=7.4 Hz, 2H), 2.50 (s,6H, under DMSO), 1.20 (t, J=7.6 Hz, 3H).

Intermediate 040b:N-(tert-Butyl)-3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(o-tolyl)thiophene-2-sulfonamide

A mixture of Intermediate 040a (0.070 g, 0.203 mmol) and Intermediate039c (0.090 g, 0.254 mmol), 2 M aqueous Na₂CO₃ (0.434 mL, 0.869 mmol)and Pd (Ph₃P)₄ (0.023 g, 0.020 mmol) in toluene-ethanol (9:1, 5 mL) wastreated as described in Example 039b. The cooled mixture was dilutedwith EtOAc, filtered through Na₂SO₄ and evaporated to give an amber gum.This material was purified by ISCO (0-100% EtOAc-DCM) to give theproduct (117 mg) as a gum. This material was taken up in DMF and wasrepurified by preparative LC (Method C) to give the title compound(Intermediate 040b, 0.082 g, 58.7% yield) as a colourless gum which wasused as such in the next step. LC (Method B): 2.211 min; HRMS (ESI):Calcd. for C₃₂H₃₇N₄O₂S₂ [M+H]⁺ m/z 573.2358; found: 573.2377; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.60 (d, J=8.2 Hz, 2H), 7.46 (d, J=7.4 Hz, 1H),7.42 (s, 1H), 7.19-7.36 (m, 6H), 7.08 (br. s., 1H), 5.57 (br. s., 2H),2.88 (d, J=7.0 Hz, 2H), 2.53 (s, 6H), 2.41 (s, 3H), 1.25 (t, J=7.4 Hz,3H), 0.96 (s, 9H).

Intermediate 040c:3-(4-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(o-tolyl)thiophene-2-sulfonamide

To a solution of Intermediate 040b (0.074 g, 0.108 mmol) in DCM (3 mL)was added anisole (0.118 mL, 1.077 mmol) and then TFA (5 mL). Themixture was stirred at RT in a sealed flask for two days and then thevolatiles were removed under reduced pressure and the residue wasevaporated from ACN solution (×2) to give a nearly colourless gum.Quantitative yield was assumed and this material Intermediate 040c wasused as such in the next step without further purification. LC-MS(APCI): Calcd. for C₂₈H₂₉N₄O₂S₂ [M+H]⁺ m/z 517.1732; found: 517.2.

Example 040: Butyl(3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(o-tolyl)thiophen-2-yl)sulfonylcarbamate

A solution of Intermediate 040c (0.034 g, 0.054 mmol) in pyridine (1 mL)was treated with triethylamine (0.056 mL, 0.405 mmol),4-(pyrrolidin-1-yl)pyridine (0.024 g, 0.162 mmol) and butylcarbonochloridate (0.021 mL, 0.162 mmol) and the reaction mixture wasstirred at RT overnight. The reaction mixture was subsequentlyevaporated to dryness to give a solid residue. The residue was taken upin DMF, the mixture was acidified with AcOH and the solution wassubmitted to preparative LC purification (Method C) to give the titlecompound (Example 040, 0.034 g, 86% yield) as a white solid. LC (MethodB): 2.202 min; HRMS (ESI): Calcd. for C₃₃H₃₇N₄O₄S₂ [M+H]⁺ m/z 617.2256;found 617.2274; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.75-7.62 (m, 1H), 7.53(d, J=7.8 Hz, 2H), 7.47 (d, J=7.4 Hz, 1H), 7.27-7.36 (m, 4H), 7.21-7.25(m, 2H), 7.07 (br s, 1H), 5.57 (br s, 2H), 3.95 (t, J=6.5 Hz, 2H), 2.89(m, 2H), 2.53 (s, 6H), 2.42 (s, 3H), 1.36-1.42 (m, 2H), 1.26 (t, J=7.4Hz, 3H), 1.15 (m, 2H), 0.77 (t, J=7.2 Hz, 3H).

Example 045: Butyl(3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(2-(trifluoromethyl)phenyl)thiophen-2-yl)sulfonylcarbamate

Intermediate 045a:N-(tert-Butyl)-5-(2-(trifluoromethyl)phenyl)thiophene-2-sulfonamide

A vial charged with 5-bromo-N-(cert-butyl)thiophene-2-sulfonamide (1.00g, 3.35 mmol), (2-(trifluoromethyl)phenyl)boronic acid (0.955 g, 5.03mmol), 2M aqueous Na₂CO₃ (4.50 mL, 10.06 mmol) and Pd (Ph₃P)₄ (0.194 g,0.168 mmol) in a mixture of toluene-ethanol (9:1, 20 mL) was reacted asdescribed in Example 039b. The crude material was pre-adsorbed on 10 gof silica gel and purified by flash chromatography (ISCO 10-40%,EtOAc-hexane) to give the title compound (Intermediate 045a, 1.141 g,3.14 mmol, 94%) as a white solid. LC-MS (Method H): 1.300 min, Calcd.for C₁₅H₁₅F₃NO₂S₂ [M−H]⁻ m/z 362.1; found 362.0; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.88 (d, J=7.4 Hz, 1H), 7.82 (s, 1H), 7.75 (d, J=7.4 Hz,1H), 7.70 (d, J=7.4 Hz, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.55 (d, J=3.9 Hz,1H), 7.13 (d, J=3.9 Hz, 1H), 1.16 (s, 9H).

Intermediate 045b:(2-(N-(tert-Butyl)sulfamoyl)-5-(2-(trifluoromethyl)phenyl)thiophen-3-yl)boronicacid

A solution of Intermediate 045a (1.12 g, 3.08 mmol) in dry THF (25 mL)was treated with a solution of 1.2 M n-BuLi in hexanes (6.42 mL, 7.70mmol) and triisopropyl borate (2.13 mL, 9.25 mmol) as described inExample 039c. The resulting turbid mixture was quenched with 2M aqueousHCl (9.91 mL, 19.83 mmol), then partitioned with EtOAc-H₂O and theorganic phase was separated, washed with H₂O and brine, dried overNa₂SO₄ and evaporated. The resulting residue was purified by ISCO(10-40%, EtOAc/Hexane) to afford the desired compound as a pale yellowfoam (Intermediate 045b, 0.717 g, 1.761 mmol, 57%). LC-MS (Method H):1.296 min, Calcd. for C₁₅H₁₇BF₃NO₄S₂ [M−H]⁻ m/z 406.1; found 406.0; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.65 (s, 2H), 7.89 (d, J=7.0 Hz, 1H), 7.75(d, J=7.4 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.4 Hz, 1H),7.29-7.34 (m, 1H), 7.25 (s, 1H), 1.19 (s, 9H).

Intermediate 045c:N-(tert-Butyl)-3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(2-(trifluoromethyl)phenyl)thiophene-2-sulfonamide

A mixture of Intermediate 045b (0.059 g, 0.145 mmol) and Intermediate040a (0.050 g, 0.145 mmol) in toluene-ethanol (9:1, 5 mL) was treated asdescribed in Example 039b. The volatiles were then evaporated and theresidue was dissolved in DMSO (4.5 mL), then H₂O (0.5 mL) was added andthe mixture was acidified with formic acid (0.10 mL). This solution wasfiltered through a 0.45 micron filter disk and purified by preparativeLC (Method F, with 0.1% HCO₂H as modifier) to give the title compound(Intermediate 045c, 0.052 g, 0.083 mmol, 57%) as a pale yellow solid.HRMS (ESI): Calcd. for C₃₂H₃₄F₃N₄O₂S₂ [M+H]⁺ m/z 627.2070; found:627.2090.

Intermediate 045d:3-(4-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(2-(trifluoromethyl)phenyl)thiophene-2-sulfonamide

A solution of Intermediate 045c (0.052 g, 0.083 mmol) in DCM (3 mL) wastreated with anisole (0.091 mL, 0.830 mmol) and TFA (5 mL) as describedin Example 040c to afford the title compound Intermediate 045dquantitatively as a TFA salt. LC-MS (Method H): 1.340 min, Calcd. forC₂₈H₂₆F₃N₄O₂S₂ [M+H]⁺ m/z 571.1; found 571.1.

Example 045: Butyl(3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(2-(trifluoromethyl)phenyl)thiophen-2-yl)sulfonylcarbamate

A solution of Intermediate 045d (0.030 g, 0.044 mmol) in pyridine (1 mL)was treated with triethylamine (0.046 mL, 0.329 mmol),4-(pyrrolidin-1-yl)pyridine (0.0195 g, 0.131 mmol) and butylcarbonochloridate (0.017 mL, 0.131 mmol) as described in Example 040.The reaction mixture was then evaporated to dryness to give a solidresidue which was taken up in DMSO (1.6 mL), acidified with formic acid(0.10 mL) and purified by preparative LC (Method F, with 0.1% of HCO₂Has modifier) to give the title compound (Example 045, 0.021 g, 0.031mmol, 72%) as a white solid. LC (Method B): 1.989 min; HRMS (ESI): Calcdfor C₃₃H₃₄F₃N₄O₄S₂ [M+H]⁺ m/z 671.1968; found 671.1907; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.90 (d, J=7.4 Hz, 1H), 7.64-7.80 (m, 4H), 7.50 (d, J=8.2Hz, 2H), 7.23 (s, 1H), 7.18 (d, J=8.2 Hz, 2H), 6.96 (s, 1H), 5.51 (s,2H), 3.93 (t, J=6.5 Hz, 2H), 2.79 (q, J=7.7 Hz, 2H), 2.51 (s, 6H),1.34-1.43 (m, 2H), 1.24 (t, J=7.4 Hz, 3H), 1.16 (m, 2H), 0.78 (t, J=7.4Hz, 3H).

Example 046: Butyl(3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(2-(trifluoromethyl)phenyl)thiophen-2-yl)sulfonylcarbamate

Intermediate 046a:N-(tert-Butyl)-3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(2-(trifluoromethyl)phenyl)thiophene-2-sulfonamide

A mixture of Intermediate 045b (0.059 g, 0.145 mmol), Intermediate 039a(0.050 g, 0.145 mmol), 2M aq. Na₂CO₃ (0.22 mL, 0.434 mmol) and Pd(Ph₃P)₄ (0.017 g, 0.014 mmol) in toluene-ethanol (9:1, 5 mL) was treatedas described in Example 039b. The volatiles were subsequently evaporatedand the residue was dissolved in DMSO (4.5 mL), then H₂O (0.5 mL) wasadded and the mixture was acidified with formic acid (0.10 mL). Thissolution was filtered through a 0.45 micron filter disk and purified bypreparative LC (Method F with 0.1% HCO₂H as modifier) to give the titlecompound (Intermediate 046a, 0.076 g, 0.121 mmol, 84%) as a pale yellowsolid. HRMS (ESI): Calcd. for C₃₁H₃₃F₃N₅O₂S₂ [M+H]⁺ m/z 628.2022; found:628.2066.

Intermediate 046b:3-(5-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(2-(trifluoromethyl)phenyl)thiophene-2-sulfonamide

A solution of Intermediate 046a (0.076 g, 0.121 mmol) in DCM (3 mL) wastreated with anisole (0.132 mL, 1.211 mmol) and TFA (5 mL) as describedin Example 40c to afford the title compound Intermediate 046bquantitatively as a TFA salt. LC-MS (Method H): 1.300 min, Calcd. forC₂₇H₂₅F₃N₅O₂S₂ [M+H]⁺ m/z 572.14; found 572.1.

Example 046: Butyl(3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(2-(trifluoromethyl)phenyl)thiophen-2-yl)sulfonylcarbamate

A solution of Intermediate 046b (0.030 g, 0.044 mmol) in pyridine (1 mL)was treated with triethylamine (0.046 mL, 0.329 mmol),4-(pyrrolidin-1-yl)pyridine (0.0195 g, 0.131 mmol) and butylcarbonochloridate (0.017 mL, 0.131 mmol) as described in Example 040.The reaction mixture was then evaporated to dryness to give a solidresidue which was taken up in DMSO (1.6 mL), acidified with formic acid(0.10 mL) and purified by preparative LC (Method F with 0.1% of HCO₂H asmodifier) to give the title compound (Example 046, 0.021 g, 0.031 mmol,71%) as a white solid. LC (Method B): 1.949 min; HRMS (ESI): Calcd forC₃₂H₃₃F₃N₅O₄S₂ [M+H]⁺ m/z 672.1921; found 672.1870; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.54 (d, J=2.0 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.85 (d,J=7.8 Hz, 1H), 7.77 (d, J=7.0 Hz, 1H), 7.61-7.75 (m, 4H), 7.52 (s, 1H),6.98 (s, 1H), 5.56 (s, 2H), 3.94 (t, J=6.7 Hz, 2H), 2.84 (q, J=7.4 Hz,2H), 2.50-2.54 (m, 6H), 1.36-1.45 (m, 2H), 1.25 (t, J=7.4 Hz, 3H),1.13-1.22 (m, 2H), 0.76 (t, J=7.4 Hz, 3H).

Example 047: Butyl(3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(2-methoxypyridin-3-yl)thiophen-2-yl)sulfonylcarbamate

Intermediate 047a:N-(tert-butyl)-5-(2-Methoxypyridin-3-yl)thiophene-2-sulfonamide

A vial charged with 5-bromo-N-(cert-butyl)thiophene-2-sulfonamide (1.00g, 3.35 mmol), (2-methoxypyridin-3-yl)boronic acid (0.769 g, 5.03 mmol),2M aqueous Na₂CO₃ (5.03 mL, 10.06 mmol) and Pd (Ph₃P)₄ (0.194 g, 0.168mmol) in a mixture of toluene-ethanol (9:1, 20 mL) was treated asdescribed in Example 039b. After cooling, the reaction mixture wasdiluted with EtOAc (100 mL) and H₂O (50 mL). The organic phase wasseparated, washed with sat. aq. NaHCO₃ and brine, then dried overNa₂SO₄, filtered and evaporated to give a dark brown gum. This materialwas pre-adsorbed on 10 g of silica gel and purified by flashchromatography (ISCO 10-50%, EtOAc-hexane) to give the title compound(Intermediate 047a, 1.050 g, 3.22 mmol, 96%) as a white solid. LC-MS(Method H): 1.250 min, Calcd. for C₁₄H₁₇N₂O₃S₂ [M−H]⁻ m/z 325.07; found325.1; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.29 (dd, J=7.6, 1.8 Hz, 1H),8.21 (dd, J=4.9, 1.8 Hz, 1H), 7.71-7.77 (m, 2H), 7.57 (d, J=3.9 Hz, 1H),7.11-7.17 (m, 1H), 4.05 (s, 3H), 1.17 (s, 9H).

Intermediate 047b:(2-(N-(tert-Butyl)sulfamoyl)-5-(2-methoxypyridin-3-yl)thiophen-3-yl)boronicacid

A solution of Intermediate 047a (1.03 g, 3.16 mmol) in dry THF (25 mL)was treated with a solution of 1.2 M n-BuLi in hexanes (6.57 mL, 7.89mmol) and triisopropyl borate (2.18 mL, 9.47 mmol) as described inExample 039c. The resulting turbid mixture was quenched with 2M aqueousHCl (9.91 mL, 19.83 mmol), then partitioned with EtOAc-H₂O and theorganic phase was separated, washed with H₂O and brine, dried overNa₂SO₄ and evaporated. The resulting residue was purified by ISCO(20-70%, EtOAc/Hexane) to afford the desired compound as a dark redsolid (Intermediate 047b, 0.275 g, 0.743 mmol, 24%). LC-MS (Method H):1.248 min, Calcd. for C₁₄H₁₈BN₂O₅S₂ [M−H]⁻ m/z 369.1; found 369.0; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.62 (s, 2H), 8.25 (dd, J=7.6, 1.8 Hz, 1H),8.20 (dd, J=4.9, 1.8 Hz, 1H), 7.86 (s, 1H), 7.23 (s, 1H), 7.14 (dd,J=7.6, 4.9 Hz, 1H), 4.04 (s, 3H), 1.18 (s, 9H).

Intermediate 047c:N-(tert-Butyl)-3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(2-methoxypyridin-3-yl)thiophene-2-sulfonamide

A mixture of Intermediate 047b (0.054 g, 0.145 mmol), Intermediate 040a(0.050 g, 0.145 mmol), 2M aq. Na₂CO₃ (0.22 mL, 0.436 mmol) and Pd(Ph₃P)₄ (0.017 g, 0.015 mmol) in toluene-ethanol (9:1, 5 mL) was treatedas described in Example 039b. The volatiles were subsequently evaporatedand the residue was dissolved in DMSO (4.5 mL), then H₂O (0.5 mL) wasadded and the mixture was acidified with formic acid (0.10 mL). Thissolution was filtered through a 0.45 micron filter disk and purified bypreparative LC (Method F with 0.1% HCO₂H as modifier) to give the titlecompound (0.054 g, 0.092 mmol, 63%) as a pale yellow solid. HRMS (ESI):Calcd. for C₃₁H₃₆N₅O₃S₂ [M+H]⁺ m/z 590.2254; found: 590.2281.

Intermediate 047d:3-(4-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(2-methoxypyridin-3-yl)thiophene-2-sulfonamide

A solution of Intermediate 047c (0.054 g, 0.092 mmol) in DCM (3 mL) wastreated with anisole (0.100 mL, 0.916 mmol) and TFA (5 mL) as describedin Example 040c to afford the title compound Intermediate 047dquantitatively as a TFA salt. LC-MS (Method H): 1.290 min, Calcd. forC₂₇H₂₈N₅O₃S₂ [M+H]⁺ m/z 534.2; found 534.1.

Example 047: Butyl(3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-(2-methoxypyridin-3-yl)thiophen-2-yl)sulfonylcarbamateA solution of Intermediate 047d (0.030 g, 0.046 mmol) in pyridine (1 mL)was treated with triethylamine (0.048 mL, 0.347 mmol),4-(pyrrolidin-1-yl)pyridine (0.021 g, 0.139 mmol) and butylcarbonochloridate (0.018 mL, 0.139 mmol) as described in Example 040.The reaction mixture was then evaporated to dryness to give a solidresidue which was taken up in DMSO (1.6 mL), acidified with formic acid(0.10 mL) and purified by preparative LC (Method F with 0.1% of HCO₂H asmodifier) to give the title compound (Example 047, 0.018 g, 0.028 mmol,61%) as a white solid. LC (Method B): 1.927 min; HRMS (ESI): Calcd forC₃₂H₃₆N₅O₅S₂ [M+H]⁺ m/z 634.2152; found 634.2088; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.37 (dd, J=7.4, 1.6 Hz, 1H), 8.22 (dd, J=5.1, 1.6 Hz,1H), 7.82 (s, 1H), 7.47-7.54 (m, J=8.2 Hz, 2H), 7.15-7.21 (m, J=8.2 Hz,2H), 7.13 (dd, J=7.6, 4.9 Hz, 1H), 6.96 (s, 1H), 5.51 (s, 2H), 4.05 (s,3H), 3.90 (t, J=6.5 Hz, 2H), 2.79 (q, J=7.4 Hz, 2H), 2.51 (s, 6H),1.32-1.40 (m, 2H), 1.25 (t, J=7.6 Hz, 3H), 1.08-1.17 (m, 2H), 0.74 (t,J=7.4 Hz, 3H).

Example 048: Butyl(3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(2-methoxypyridin-3-yl)thiophen-2-yl)sulfonylcarbamate

Intermediate 048a:N-(tert-Butyl)-3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(2-methoxypyridin-3-yl)thiophene-2-sulfonamide

A mixture of Intermediate 047b (0.054 g, 0.145 mmol), Intermediate 039a(0.050 g, 0.145 mmol), 2M aq. Na₂CO₃ (0.22 mL, 0.434 mmol) and Pd(Ph₃P)₄ (0.017 g, 0.015 mmol) in toluene-ethanol (9:1, 5 mL) was treatedas described in Example 039c. The volatiles were then evaporated and theresidue was dissolved in DMSO (4.5 mL), then H₂O (0.5 mL) was added andthe mixture was acidified with formic acid (0.10 mL). This solution wasfiltered through a 0.45 micron filter disk and purified by preparativeLC (Method F with 0.1% HCO₂H as modifier) to give the title compound(Intermediate 048a, 0.060 g, 0.102 mmol, 70%) as a pale yellow solid.HRMS (ESI): Calcd. for C₃₀H₃₅N₆O₃S₂ [M+H]⁺ m/z 591.2207; found:591.2230.

Intermediate 048b:3-(5-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(2-methoxypyridin-3-yl)thiophene-2-sulfonamide

A solution of Intermediate 048a (0.060 g, 0.102 mmol) in DCM (3 mL) wastreated with anisole (0.111 mL, 1.016 mmol) and TFA (5 mL) as describedin Example 040c to afford the title compound Intermediate 048bquantitatively as a TFA salt. LC-MS (Method H): 1.258 min, Calcd. forC₂₆H₂₇N₆O₃S₂ [M+H]⁺ m/z 535.16; found 535.1.

Example 048: Butyl(3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-(2-methoxypyridin-3-yl)thiophen-2-yl)sulfonylcarbamate

A solution of Intermediate 048b (0.030 g, 0.046 mmol) in pyridine (1 mL)was treated with triethylamine (0.048 mL, 0.347 mmol),4-(pyrrolidin-1-yl)pyridine (0.021 g, 0.139 mmol) and butylcarbonochloridate (0.018 mL, 0.139 mmol) as described in Example 040.The reaction mixture was then evaporated to dryness to give a solidresidue which was taken up in DMSO (1.6 mL), acidified with formic acid(0.10 mL) and purified by preparative LC (Method F with 0.1% of HCO₂H asmodifier) to give the title compound (Example 048, 0.017 g, 0.027 mmol,58%) as a white solid. LC (Method B): 1.907 min; HRMS (ESI): Calcd forC₃₁H₃₅N₆O₅S₂ [M+H]⁺ m/z 635.2105; found 635.2051; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.54 (d, J=2.0 Hz, 1H), 8.39 (dd, J=7.6, 1.8 Hz, 1H),8.23 (dd, J=4.7, 1.6 Hz, 1H), 8.08 (s, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.66(dd, J=8.2, 2.3 Hz, 1H), 7.14 (dd, J=7.6, 4.9 Hz, 1H), 6.97 (s, 1H),5.56 (s, 2H), 4.06 (s, 3H), 3.92 (t, J=6.5 Hz, 2H), 2.84 (q, J=7.4 Hz,2H), 2.51 (d, J=2.0 Hz, 6H), 1.34-1.42 (m, 2H), 1.26 (t, J=7.4 Hz, 3H),1.09-1.20 (m, 2H), 0.73 (t, J=7.4 Hz, 3H).

Example 049: Butyl(3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-phenylthiophen-2-yl)sulfonylcarbamate

Intermediate 049a N-(tert-Butyl)-5-phenylthiophene-2-sulfonamide

A vial charged with 5-bromo-N-(tert-butyl)thiophene-2-sulfonamide (1.00g, 3.35 mmol), phenylboronic acid (0.825 g, 5.03 mmol), 2M aqueousNa₂CO₃ (5.03 mL, 10.06 mmol) and Pd (Ph₃P)₄ (0.194 g, 0.168 mmol) in amixture of toluene-ethanol (9:1, 20 mL) was treated as described inExample 39b. After cooling, the reaction mixture was diluted with EtOAc(100 mL) and H₂O (50 mL). The organic phase was separated, washed withsat. aq. NaHCO₃ and brine, then dried over Na₂SO₄, filtered andevaporated to give a dark brown gum. This material was pre-adsorbed on10 g of silica gel and purified by flash chromatography (ISCO 10-40%,EtOAc-hexane) to give the title compound (Intermediate 049a, 0.977 g,3.31 mmol, 99%) as a white solid. LC-MS (Method H): 1.280 min, Calcd.for C₁₄H₁₆NO₂S₂ [M−H]⁻ m/z 294.06; found 294.0; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.80 (s, 1H), 7.69-7.75 (m, 2H), 7.54-7.57 (m, 1H),7.51-7.54 (m, 1H), 7.43-7.50 (m, 2H), 7.37-7.43 (m, 1H), 1.19 (s, 9H).

Intermediate 049b:(2-(N-(tert-Butyl)sulfamoyl)-5-phenylthiophen-3-yl)boronic acid

A solution of Intermediate 049a (0.950 g, 3.22 mmol) in dry THF (25 mL)was treated with a solution of 1.2 M n-BuLi in hexanes (6.70 mL, 8.04mmol) and triisopropyl borate (2.23 mL, 9.65 mmol) as described inExample 039c. The resulting turbid mixture was quenched with 2M aqueousHCl (9.91 mL, 19.83 mmol) then partitioned with EtOAc-H₂O and theorganic phase was separated, washed with H₂O and brine, dried overNa₂SO₄ and evaporated. The residue was purified by ISCO (20-60%,EtOAc/Hexane) to afford the title compound as a pale yellow solid(Intermediate 049b, 0.681 g, 2.007 mmol, 62%). LC-MS (Method H): 1.281min, Calcd. for C₁₄H₁₇BNO₄S₂ 338.07; found 338.0; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.62 (s, 2H), 7.67-7.72 (m, 2H), 7.63 (s, 1H), 7.42-7.49(m, 2H), 7.33-7.42 (m, 1H), 7.25 (s, 1H), 1.20 (s, 9H).

Intermediate 049c:N-(tert-Butyl)-3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-phenylthiophene-2-sulfonamide

A mixture of Intermediate 049b (0.049 g, 0.145 mmol), Intermediate 040a(0.050 g, 0.145 mmol), 2M aq. Na₂CO₃ (0.22 mL, 0.436 mmol) and Pd(Ph₃P)₄ (0.017 g, 0.015 mmol) in toluene-ethanol (9:1, 5 mL) was treatedas described in Example 039b. The volatiles were then evaporated and theresidue was dissolved in DMSO (4.5 mL), then H₂O (0.5 mL) was added andthe mixture was acidified with formic acid (0.10 mL). This solution wasfiltered through a 0.45 micron filter disk and purified by preparativeLC (Method F with 0.1% HCO₂H as modifier) to give the title compound(Intermediate 049c, 0.059 g, 0.106 mmol, 73%) as a pale yellow solid.HRMS (ESI): Calcd. for C₃₁H₃₅N₄O₂S₂ [M+H]⁺ m/z 559.2196; found:559.2227.

Intermediate 049d:3-(4-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-phenylthiophene-2-sulfonamide

A solution of Intermediate 049c (0.059 g, 0.106 mmol) in DCM (3 mL) wastreated with anisole (0.115 mL, 1.056 mmol) and TFA (5 mL) as describedin Example 040c to afford the title compound Intermediate 049dquantitatively as a TFA salt. LC-MS (Method H): 1.323 min, Calcd. forC₂₇H₂₇N₄O₂S₂ [M+H]⁺ m/z 503.16; found 503.1.

Example 049: Butyl(3-(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)phenyl)-5-phenylthiophen-2-yl)sulfonylcarbamate

A solution of Intermediate 049d (0.030 g, 0.049 mmol) in pyridine (1 mL)was treated with triethylamine (0.051 mL, 0.365 mmol),4-(pyrrolidin-1-yl)pyridine (0.022 g, 0.146 mmol) and butylcarbonochloridate (0.019 mL, 0.146 mmol) as described in Example 040.The reaction mixture was subsequently evaporated to dryness to give asolid residue which was taken up in DMSO (1.6 mL), acidified with formicacid (0.10 mL) and purified by preparative LC (Method F, with 0.1% ofHCO₂H as modifier) to give the title compound (Example 049, 0.023 g,0.038 mmol, 78%) as a white solid. LC (Method B): 1.967 min; HRMS (ESI):Calcd for C₃₂H₃₅N₄O₄S₂ [M+H]⁺ m/z 603.2094; found 603.2052; ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.72-7.78 (m, 2H), 7.62 (s, 1H), 7.50-7.56 (m, 2H),7.38-7.49 (m, 4H), 7.15-7.21 (m, 2H), 6.96 (s, 1H), 5.51 (s, 2H), 3.91(t, J=6.5 Hz, 2H), 2.79 (d, J=7.4 Hz, 2H), 2.51 (s, 6H), 1.32-1.41 (m,2H), 1.25 (t, J=7.4 Hz, 3H), 1.09-1.16 (m, 2H), 0.75 (t, J=7.2 Hz, 3H).

Example 050: Butyl(3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-phenylthiophen-2-yl)sulfonylcarbamate

Intermediate 050a:N-(tert-Butyl)-3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-phenylthiophene-2-sulfonamide

A mixture of Intermediate 049b (0.049 g, 0.145 mmol), Intermediate 039a(0.050 g, 0.145 mmol), 2M aq. Na₂CO₃ (0.22 mL, 0.434 mmol) and Pd(Ph₃P)₄ (0.017 g, 0.014 mmol) in toluene-ethanol (9:1, 5 mL) was treatedas described in Example 039b. The volatiles were then evaporated and theresidue was dissolved in DMSO (4.5 mL), then H₂O (0.5 mL) was added andthe mixture was acidified with formic acid (0.10 mL). This solution wasfiltered through a 0.45 micron filter disk and purified by preparativeLC (Method F with 0.1% HCO₂H as modifier) to give the title compound(Example 050a, 0.072 g, 0.129 mmol, 89%) as a pale yellow solid. HRMS(ESI): Calcd. for C₃₀H₃₄N₅O₂S₂ [M+H]⁺ m/z 560.2148; found: 560.2168.

Intermediate 050b:3-(5-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-phenylthiophene-2-sulfonamide

A solution of Intermediate 050a (0.072 g, 0.129 mmol) in DCM (3 mL) wastreated with anisole (0.141 mL, 1.286 mmol) and TFA (5 mL), as describedin Example 040c to afford the title compound Example 050b quantitativelyas a 2.TFA salt. LC-MS (Method H): 1.288 min, Calcd. for C₂₆H₂₆N₅O₂S₂[M+H]⁺ m/z 504.15; found 504.0.

Example 050: butyl(3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-5-phenylthiophen-2-yl)sulfonylcarbamate

A solution of Intermediate 050b (0.030 g, 0.049 mmol) in pyridine (1 mL)was treated with triethylamine (0.051 mL, 0.364 mmol),4-(pyrrolidin-1-yl)pyridine (0.022 g, 0.146 mmol) and butylcarbonochloridate (0.019 mL, 0.146 mmol) as described in Example 040.The reaction mixture was subsequently evaporated to dryness to give asolid residue which was taken up in DMSO (1.6 mL), acidified with formicacid (0.10 mL) and purified by preparative LC (Method F with 0.1% ofHCO₂H as modifier) to give the title compound (Example 050, 0.022 g,0.036 mmol, 75%) as a white solid. LC (Method B): 1.930 min; HRMS (ESI):Calcd for C₃₁H₃₄N₅O₄S₂ [M+H]⁺ m/z 604.2047; found 604.2082; ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.54 (d, J=1.6 Hz, 1H), 7.82-7.90 (m, 2H), 7.73-7.80(m, 2H), 7.67 (dd, J=8.2, 2.3 Hz, 1H), 7.37-7.51 (m, 4H), 6.98 (s, 1H),5.56 (s, 2H), 3.93 (t, J=6.5 Hz, 2H), 2.85 (q, J=7.4 Hz, 2H), 2.51 (2s,6H), 1.34-1.42 (m, 2H), 1.26 (t, J=7.4 Hz, 3H), 1.14 (d, J=7.4 Hz, 2H),0.74 (t, J=7.4 Hz, 3H).

Example 051:3-((5′-(3,3-Difluoropyrrolidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a vial charged with 2nd generation RuPhos precatalyst (4.78 mg, 6.16mol) was added Intermediate 001j (30 mg, 0.041 mmol) and sodiumtert-butoxide (15.78 mg, 0.164 mmol). THF (1 mL) was then added followedby 3,3-difluoropyrrolidine, HCl (17.68 mg, 0.123 mmol). The reactionvial was sealed and heated at 65° C. for 1.5 h. The crude reactionmixture was then diluted with EtOAc, filtered over Celite® andconcentrated to a brown residue. This crude intermediate was retaken DCM(2 mL) and subjected to triethylsilane (0.032 mL, 0.198 mmol) followedby TFA (0.092 mL, 1.189 mmol). After 10 min of stirring at RT, thereaction mixture was concentrated, retaken in DMF, filtered and purifiedby preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 15-55% B over 20 minutes, then a3-minute hold at 100% B; Flow: 20 mL/min.) to afford 7.2 mg (0.013 mmol,34% yield) of the title compound Example 051. LC-MS (Method A2): 0.76min, [M+H]⁺=515.0; ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.43 (d, J=8.2 Hz,1H), 7.08 (d, J=7.9 Hz, 2H), 6.98 (d, J=7.9 Hz, 2H), 6.94 (s, 1H), 6.68(d, J=8.2 Hz, 1H), 6.52 (s, 1H), 5.43 (s, 2H), 3.75 (t, J=13.3 Hz, 2H),3.53 (t, J=7.2 Hz, 2H), 2.79 (q, J=7.4 Hz, 2H), 2.51 (s, 6H), 1.26 (t,J=7.3 Hz, 3H).

The compounds listed in the table below were synthesized using the samemethods that were used to prepare Example 001.

LC-MS m/z Ex [M + H]⁺; # Structure MW RT (Method) ¹H NMR 052

486.570 487.0; 1.31 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (brs, 1H), 8.60 (br s, 1H), 8.20 (br d, J = 7.3 Hz, 1H), 7.85 (br d, J =7.3 Hz, 1H), 7.74 (br s, 2H), 7.51 (br s, 1H), 7.15 (br d, J = 7.3 Hz,2H), 7.04 (br d, J = 7.6 Hz, 2H), 6.95 (s, 1H), 5.45 (s, 2H), 2.78 (q, J= 7.5 Hz, 2H), 2.53 (d, J = 19.5 Hz, 6H), 1.29-1.19 (m, 3H) (1exchangeable proton not observed) 053

521.563 522.3; 0.85 (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (d, J =7.9 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 7.2Hz, 2H), 7.27 (t, J = 9.1 Hz, 1H), 7.15 (d, J = 7.8 Hz, 2H), 7.04 (d, J= 7.9 Hz, 2H), 6.95 (s, 1H), 5.46 (s, 2H), 2.78 (q, J = 7.4 Hz, 2H),2.55 (s, 6H), 1.24 (t, J = 7.4 Hz, 3H) (1 exchangeable proton notobserved) 054

521.563 522.0; 0.86 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ7.77-7.68 (m, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.53 (s, 1H), 7.40 (t, J =10.1 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.02(d, J = 7.9 Hz, 2H), 6.94 (s, 1H), 5.45 (s, 2H), 2.77 (q, J = 7.3 Hz,2H), 2.55 (s, 6H), 1.24 (t, J = 7.4 Hz, 3H) (1 exchangeable proton notobserved)

Example 055:2-butyl-3-((4″-methyl-6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 055a:4′-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-chloro-[1,1′-biphenyl]-2-carbonitrile

Intermediate 001d (1 g, 2.56 mmol), 4-bromo-2-iodobenzonitrile (0.944 g,3.07 mmol), and PdCl₂(dppf)-CH₂Cl₂ Adduct (0.209 g, 0.256 mmol) weredissolved in toluene (20.4 mL), ethanol (5.11 mL), and tripotassiumphosphate (2 M aq, 2.56 mL, 5.11 mmol) and the reaction was degassed for15 minutes by bubbling with N₂. The reaction was sealed and heated at100° C. for 18 hours. The reaction was cooled to ambient temperature,filtered through celite, diluted with EtOAc, washed with saturatedNaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was purified by column chromatography (ISCO, 80 gsilica gel column, 29 minute gradient of 0 to 100% EtOAc in hexanes) toyield Intermediate 055a (0.649 g, 1.49 mmol, 57%) as a tan solid. LC-MS(Method A2) RT=0.85 min, MS (ESI) m/z: 445 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.66 (d, J=1.4 Hz, 1H), 7.64-7.58 (m, 2H), 7.51-7.47 (m, 2H),7.27 (d, J=8.3 Hz, 2H), 6.94 (s, 1H), 5.55 (s, 2H), 2.84 (q, J=7.4 Hz,2H), 2.67 (s, 3H), 2.62 (s, 3H), 1.36 (t, J=7.6 Hz, 3H)

Intermediate 055b:4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-chloro-[1,1′-biphenyl]-2-carbonitrile

Intermediate 055a (0.649 g, 1.46 mmol) was dissolved in toluene (14.6mL). Dibutyltin oxide (0.363 g, 1.46 mmol) and TMS-N₃ (1.94 mL, 14.6mmol) were added and the reaction sealed in a pressure vial and heatedat 100° C. for 18 hours. The reaction was cooled to ambient temperatureand diluted with EtOAc into an erlenmeyer. A 10% aqueous solution of CAN(9.60 g, 17.5 mmol) was added slowly to mild bubbling. An aliquot of thereaction was added to an aqueous 0.02 M FeCl₃ solution to confirmcomplete consumption of azide (no red color). The layers were separatedand the organic layer was further washed twice with saturated NH₄Cl,then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Thecrude material was purified by column chromatography (ISCO, 40 g silicagel olumn, 19 minute gradient of 0 to 20% MeOH in DCM) to giveIntermediate 055b (0.580 g, 1.19 mmol, 81%) as a tan solid. LC-MS(Method A2) RT=0.76 min, MS (ESI) m/z: 486 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.83 (d, J=8.4 Hz, 1H), 7.64 (dd, J=8.4, 2.0 Hz, 1H), 7.55 (d,J=1.8 Hz, 1H), 7.11-7.04 (m, 2H), 7.03-6.97 (m, 2H), 6.93 (s, 1H), 5.44(s, 2H), 3.48 (s, 1H), 2.71 (q, J=7.6 Hz, 2H), 2.57 (s, 3H), 2.49 (s,3H), 1.17 (t, J=7.5 Hz, 3H)

Intermediate 055c:4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-chloro-[1,1′-biphenyl]-2-carbonitrile

Intermediate 055b (580 mg, 1.19 mmol), TEA (215 μL, 1.54 mmol) andtrityl chloride (381 mg, 1.37 mmol) were dissolved in DCM (5.94 mL).After 1 hour, the reaction was diluted with DCM and washed with 1MK₂HPO₄, then brine, then dried (Na₂SO₄), filtered, and concentrated invacuo. The crude material was purified by column chromatography (ISCO,80 g silica gel column, 29 minute gradient of 0 to 100% EtOAc inhexanes) to give Intermediate 055c (707 mg, 0.97 mmol, 81%) as a clearoil. LC-MS (Method A2) RT=1.07 min, MS (ESI) m/z: 731 (M+H)⁺. ¹H NMR(500 MHz, CDCl₃) δ 7.84 (d, J=8.3 Hz, 1H), 7.60 (dd, J=8.3, 1.9 Hz, 1H),7.52 (d, J=1.9 Hz, 1H), 7.37-7.32 (m, 4H), 7.28-7.25 (m, 5H), 7.05 (d,J=8.3 Hz, 2H), 6.96-6.87 (m, 9H), 5.38 (s, 2H), 2.74-2.66 (m, 5H), 2.60(s, 3H), 1.31-1.25 (m, 3H)

Intermediate 055d:4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-chloro-[1,1′-biphenyl]-2-carbonitrile

Intermediate 055c (1.46 g, 2.00 mmol), bispinacolatodiboron (760 mg,2.99 mmol), and KOAc (492 mg, 4.99 mmol) were dissolved in 1,4-dioxane(20 mL) and degassed for 5 minutes by bubbling with Ar.PdCl₂(dppe-CH₂Cl₂ adduct (130 mg, 0.159 mmol) was added and the reactiondegassed for an additional 10 minutes. The reaction was heated at 130°C. in the microwave for 60 minutes. The reaction was diluted with EtOAcand washed with H₂O then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 80 g silica gel column, 29 minute gradient of 0 to100% EtOAc in hexanes) to give Intermediate 055d (1.03 g, 1.32 mmol,66%) as a white solid. LC-MS (Method A2) RT=1.11 min, MS (ESI) m/z:778.7 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.97 (d, J=7.4 Hz, 1H), 7.88(dd, J=7.7, 1.1 Hz, 1H), 7.77 (s, 1H), 7.38-7.31 (m, 4H), 7.30-7.22 (m,4H), 7.07 (d, J=8.3 Hz, 2H), 6.93 (br d, J=7.4 Hz, 8H), 6.87 (d, J=8.3Hz, 2H), 5.37 (s, 2H), 2.74-2.65 (m, 5H), 2.60 (s, 3H), 1.33-1.24 (m,15H)

Example 055

Intermediate 055d was reacted with 3-bromothiophene in a methodanalogous to Example 122 to give Example 055. LC-MS (Method A1) RT=1.41min, MS (ESI) 492.2 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (s, 1H),7.78 (br d, J=6.7 Hz, 1H), 7.68 (s, 1H), 7.65-7.59 (m, 3H), 7.12 (br d,J=7.9 Hz, 2H), 7.02 (br d, J=8.2 Hz, 2H), 6.95 (s, 1H), 5.44 (s, 2H),2.79 (q, J=7.6 Hz, 2H), 2.53 (d, J=18.6 Hz, 6H), 1.25 (t, J=7.5 Hz, 3H)(1 exchangeable proton not observed).

The compounds listed in the table below were synthesized using the samemethods that were used to prepare Example 055.

LC-MS m/z Ex [M + H]⁺; # Structure MW RT (Method) ¹H NMR 056

492.598 493.1; 1.43 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.13 (brd, J = 8.2 Hz, 1H), 8.01 (d, J = 3.4 Hz, 2H), 7.89 (d, J = 3.1 Hz, 1H),7.82 (d, J = 7.9 Hz, 1H), 7.16 (s, 1H), 7.16-7.12 (m, 2H), 7.12-7.08 (m,2H), 5.49 (s, 2H), 2.79 (q, J = 7.3 Hz, 2H), 2.57-2.48 (m, 6H), 1.22 (t,J = 7.5 Hz, 3H) (1 exchangeable proton not observed) 057

492.598 493.1; 1.46 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (brd, J = 4.6 Hz, 1H), 8.20 (br s, 1H), 8.09 (br s, 2H), 7.95 (s, 1H),7.23-7.00 (m, 4H), 6.95 (s, 1H), 5.45 (br s, 2H), 2.77 (br s, 2H), 2.53(br d, J = 18.9 Hz, 6H), 1.23 (br s, 3H) (1 exchangeable proton notobserved) 058

489.574 490.2; 1.17 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 9.18 (s,1H), 8.02 (s, 1H), 7.90-7.82 (m, 2H), 7.76 (s, 1H), 7.20- 7.13 (m, 2H),7.12-7.06 (m, 3H), 5.55 (s, 2H), 3.94 (s, 3H), 2.95-2.87 (m, 2H),2.59-2.47 (m, 6H), 1.24 (t, J = 7.3 Hz, 3H) (1 exchangeable proton notobserved) 059

500.610 501.4; 1.39 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.16 (brd, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.78 (t, J =7.6 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 7.13(d, J = 7.9 Hz, 2H), 7.05 (br d, J = 8.2 Hz, 2H), 6.95 (s, 1H), 5.46 (s,2H), 2.78 (q, J = 7.3 Hz, 2H), 2.59-2.48 (m, 9H), 1.28- 1.19 (m, 3H) (1exchangeable proton not observed) 060

500.610 501.2; 1.38 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.11 (brs, 1H), 7.93 (br d, J = 8.2 Hz, 1H), 7.83 (s, 1H), 7.78 (br d, J = 7.9Hz, 1H), 7.19 (s, 1H), 7.17-7.13 (m, 2H), 7.12-7.05 (m, 4H), 5.48 (s,2H), 2.80 (q, J = 7.6 Hz, 2H), 2.60-2.46 (m, 6H), 2.39 (s, 3H), 1.26-1.20 (m, 3H) (1 exchangeable proton not observed) 061

554.568 555.3; 1.59 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (d,J = 7.9 Hz, 1H), 8.33-8.28 (m, 1H), 8.23 (br t, J = 7.9 Hz, 1H), 8.20(s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.20-7.10(m, 5H), 5.51 (s, 2H), 2.83 (q, J = 7.6 Hz, 2H), 2.60-2.46 (m, 6H), 1.23(br t, J = 7.5 Hz, 3H) (1 exchangeable proton not observed)

Example 062:2-Ethyl-3-((5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 062a:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 055a (2.18 g, 4.90 mmol), bispinacolatodiboron (2.49 g,9.80 mmol), X-PHOS (0.234 g, 0.490 mmol), Pd₂(dba)₃ (0.449 g, 0.490mmol), and KOAc (2.40 g, 24.5 mmol) were dissolved in 1,4-dioxane (49.0mL). The reaction was heated at 105° C. After 1 hour, the reaction wascooled to ambient temperature and diluted with EtOAc, filtered throughcelite, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 80 g silica gel column, 19 minute gradientof 0 to 100% EtOAc in hexanes) to give Intermediate 062a (1.49 g, 2.41mmol, 62%) as a yellow solid. LC-MS (Method A2) RT=0.96 min, MS (ESI)m/z: 493.2 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.90 (s, 1H), 7.85 (d,J=7.7 Hz, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.52 (d, J=8.3 Hz, 2H), 7.25 (d,J=8.3 Hz, 2H), 6.93 (s, 1H), 5.55 (s, 2H), 2.85 (q, J=7.4 Hz, 2H), 2.67(s, 3H), 2.63 (s, 3H), 1.39-1.33 (m, 15H).

Intermediate 062b:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(4-methoxypyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 062a (50 mg, 0.102 mmol), 2-bromo-4-methoxypyridine (57.3mg, 0.305 mmol), and 2nd generation XPHOS precatalyst (7.99 mg, 10.2μmol) were dissolved in toluene (1.62 mL), ethanol (406 μL), andtripotassium phosphate (2 M aq, 102 μL, 0.203 mmol). The reaction washeated at 100° C. After 2 hours, the reaction was cooled to ambienttemperature and diluted with EtOAc, filtered through celite andconcentrated in vacuo. The crude material was purified by columnchromtography (ISCO, 24 g silica gel column, 19 minute gradient of 0 to100% EtOAc in hexanes) to give Intermediate 062b (17.7 mg, 0.037 mmol,37%) as a yellow oil. LC-MS (Method A2) RT=0.68 min, MS (ESI) m/z: 474.1(M+H)⁺.

Example 062

Intermediate 062b (17.7 mg, 0.038 mmol), dibutyltin oxide (18.9 mg,0.076 mmol), and TMS-N₃ (25.2 μL, 0.190 mmol) were dissolved in toluene(760 μL) and heated at 100° C. for 18 hours. The reaction was cooled toambient temperature then diluted with MeOH and concentrated in vacuo.The crude material was purified via preparative LC-MS with the followingconditions: Column XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with10 mM NH₄OAc; Gradient: 10-50% B over 19 minutes, then a 5-minute holdat 100% B; Flow: 20 mL/min to give Example 062 (6.4 mg, 32%). LC-MS(Method A2) RT=0.62 min, MS (ESI) m/z: 517.1 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.49 (d, J=5.6 Hz, 1H), 8.18 (br d, J=8.1 Hz, 1H), 8.12 (s,1H), 7.75 (d, J=8.1 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.16 (d, J=8.1 Hz,2H), 7.07 (d, J=8.1 Hz, 2H), 6.97 (dd, J=5.6, 2.3 Hz, 1H), 6.94 (s, 1H),5.46 (s, 2H), 3.93 (s, 3H), 2.79 (q, J=7.5 Hz, 2H), 2.59-2.48 (m, 6H),1.26 (t, J=7.4 Hz, 3H) (1 exchangeable proton not observed)

The compounds listed in the table below were synthesized using the samemethods that were used to prepare Example 62.

LC-MS m/z Ex [M + H]⁺; RT # Structure MW (Method) ¹H NMR 063

515.621 516.3; 0.72 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (s,1H), 7.83-7.66 (m, 5H), 7.43 (br d, J = 7.9 Hz, 2H), 7.15 (br d, J = 7.9Hz, 2H), 7.06 (br d, J = 7.9 Hz, 2H), 6.96 (s, 1H), 5.46 (s, 2H), 4.56(s, 2H), 2.90 (s, 3H), 2.79 (q, J = 7.5 Hz, 2H), 2.74 (s, 3H), 1.25 (t,J = 7.5 Hz, 3H) (1 exchangeable proton not observed) 064

500.610 501.1; 0.63 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (d,J = 4.9 Hz, 1H), 8.14 (dd, J = 8.0, 1.4 Hz, 1H), 8.07 (s, 1H), 7.91 (s,1H), 7.75 (d, J = 8.0 Hz, 1H), 7.20 (br d, J = 4.7 Hz, 1H), 7.16 (d, J =8.1 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.94 (s, 1H), 5.46 (s, 2H), 2.80(q, J = 7.4 Hz, 2H), 2.58-2.49 (m, 6H), 2.40 (s, 3H), 1.27 (t, J = 7.4Hz, 3H) (1 exchangeable proton not observed) 065

504.573 505.1; 0.78 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (d,J = 2.8 Hz, 1H), 8.24-8.15 (m, 2H), 8.12 (s, 1H), 7.83 (td, J = 8.8, 2.9Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.20- 7.13 (m, 2H), 7.11-7.04 (m,2H), 6.95 (s, 1H), 5.47 (s, 2H), 2.78 (q, J = 7.5 Hz, 2H), 2.61-2.47 (m,6H), 1.25 (br t, J = 1A Hz, 3H) (1 exchangeable proton not observed) 066

518.600 519.1; 1.57 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (s,1H), 8.14-8.05 (m, 2H), 8.01 (s, 1H), 7.75 (br d, J = 8.3 Hz, 1H), 7.16(br d, J = 8.0 Hz, 2H), 7.05 (br d, J = 8.1 Hz, 2H), 6.94 (s, 1H), 5.46(s, 2H), 2.80 (q, J = 7.2 Hz, 2H), 2.61-2.47 (m, 6H), 2.37 (s, 3H),1.30-1.24 (m, 3H) (1 exchangeable proton not observed) 067

536.591 537.1; 0.80 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 8.87 (d,J = 4.9 Hz, 1H), 8.33-8.25 (m, 2H), 8.20 (d, J = 1.3 Hz, 1H), 7.81 (brd, J = 8.0 Hz, 1H), 7.59 (br d, J = 4.8 Hz, 1H), 7.28-7.00 (m, 5H), 6.95(s, 1H), 5.47 (s, 2H), 2.79 (q, J = 7.5 Hz, 2H), 2.60-2.47 (m, 6H), 1.25(br t, J = 7.5 Hz, 3H) (1 exchangeable proton not observed) 068

506.632 507.2; 0.78 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.90 (brd, J = 7.0 Hz, 1H), 7.79 (s, 1H), 7.71 (br d, J = 7.9 Hz, 1H), 7.61 (s,1H), 7.10 (br d, J = 7.9 Hz, 2H), 7.01 (br d, J = 7.9 Hz, 2H), 6.96 (s,1H), 5.44 (s, 2H), 2.77 (q, J = 7.3 Hz, 2H), 2.59-2.45 (m, 9H), 1.22 (t,J = 7.5 Hz, 3H) (1 exchangeable proton not observed)

Example 069:2-((4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)oxy)aceticacid

Intermediate 069a: Methyl 2-((3-bromo-[1,1′-biphenyl]-4-yl)oxy)acetate

To a solution of 3-bromo[1,1′-biphenyl]-4-ol (100 mg, 0.401 mmol) in DMF(2.01 mL) was added potassium carbonate (166 mg, 1.20 mmol) followed bymethyl bromoacetate (41.8 μL, 0.442 mmol). The reaction was stirredvigorously at RT. After 30 min, the reaction mixture was diluted withEtOAc, filtered over celite and washed with 10% LiCl (aq). The organicphase was dried over MgSO₄, filtered and concentrated in vacuo to giveIntermediate 069a (117 mg, 0.364 mmol, 91% yield) as a white amorphoussolid. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=2.2 Hz, 1H), 7.54-7.49 (m,2H), 7.46 (dd, J=8.5, 2.3 Hz, 1H), 7.44-7.39 (m, 2H), 7.36-7.30 (m, 1H),6.88 (d, J=8.6 Hz, 1H), 4.75 (s, 2H), 3.82 (s, 3H).

Example 069

To a solution of Intermediate 001d (40 mg, 0.102 mmol) and Intermediate069a (36.1 mg, 0.112 mmol) in dioxane (2 mL) was added tripotassiumphosphate (2 M aq, 102 μL, 0.204 mmol) followed by PdCl₂(dppf) (7.48 mg,10.2 μmol). The resulting mixture was sparged with N₂ for 2 min beforebeing sealed and heated at 120° C. for 45 min in the microwave. Theorganic phase was diluted with EtOAc and filtered over a mixture ofMgSO₄/Celite. The filtrate was concentrated, dissolved in a 2:1 mixtureof THF (2 mL) and LiOH (1 M aq, 1.02 mL, 1.02 mmol) and heated at 65° C.After 30 mM the reaction mixture was quenched with Sat. NH₄Cl anddiluted with EtOAc. The organic phase was concentrated in vacuo andpurified via preparative LC-MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂Owith 0.1% TFA; Mobile Phase B: 95:5 ACN: H₂O with 10.1% TFA; Gradient:30-70% B over 27 minutes, then a 3-minute hold at 100% B; Flow: 20mL/min. The material was repurified via preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 25-50% B over 25 minutes, then a2-minute hold at 100% B; Flow: 20 mL/min to give Example 69 (11 mg,0.021 mmol, 21%). LC-MS (Method A2) RT=0.86 min, MS (ESI) m/z: 492.1(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.64 (t, J=9.0 Hz, 4H), 7.57 (d,J=8.5 Hz, 1H), 7.53 (s, 1H), 7.42 (t, J=7.3 Hz, 2H), 7.35-7.27 (m, 1H),7.17 (d, J=7.9 Hz, 2H), 7.04 (d, J=8.5 Hz, 1H), 6.96 (s, 1H), 5.51 (s,2H), 4.68 (br. s., 2H), 2.85 (q, J=7.3 Hz, 2H), 2.52 (br. s., 3H), 2.51(br. s., 3H), 1.29 (t, J=7.3 Hz, 3H) (1 exchangeable proton notobserved).

Example 070:3-((6′-(2H-Tetrazol-5-yl)-2″,3″,4″,5″-tetrahydro-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a microwave vial containing PdCl₂(dppf) (2.00 mg, 2.74 mol) andcyclohex-1-en-1-ylboronic acid (6.90 mg, 0.055 mmol) was added asolution of Intermediate 055c (20 mg, 0.027 mmol) in toluene (1 mL)followed by ethanol (250 μL) and tripotassium phosphate (2 M aq, 34.2μL, 0.068 mmol). N₂ was sparged through the reaction mixture for 5 minbefore the vial was sealed and heated at 120° C. in the microwave for 30min. The solution was then filtered over a pad of Celite/MgSO₄ thenconcentrated in vacuo. The crude residue was dissolved in DCM (2 mL),and triethylsilane (21.9 μL, 0.137 mmol) was added followed by TFA (63.3μL, 0.821 mmol). After 5 minutes, the reaction mixture was concentratedin vacuo and purified via preparative LC-MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with10 mM NH₄OAc; Gradient: 20-60% B over 20 minutes, then a 4-minute holdat 100% B; Flow: 20 mL/min to give Example 070 (4.9 mg, 0.010 mmol,37%). LC-MS (Method A2) RT=0.93 min, MS (ESI) m/z: 490.4 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 7.61-7.49 (m, 2H), 7.42 (br. s., 1H), 7.10-6.99 (m,4H), 6.95 (s, 1H), 6.33 (br. s., 1H), 5.45 (br. s., 2H), 2.77 (q, J=7.0Hz, 2H), 2.55 (s, 6H), 2.41 (br. s., 2H), 2.19 (br. s., 2H), 1.73 (br.s., 2H), 1.61 (br. s., 2H), 1.23 (t, J=7.0 Hz, 3H.

Example 071:3-((5′-Cyclohexyl-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 71a:2-ethyl-5,7-dimethyl-3-((6′-(2-trityl-2H-tetrazol-5-yl)-2″,3″,4″,5″-tetrahydro-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a microwave vial containing PdCl₂(dppf) (3.00 mg, 4.11 mol) andcyclohex-1-en-1-ylboronic acid (10.34 mg, 0.082 mmol) was added asolution of Intermediate 55c (30 mg, 0.041 mmol) in toluene (1 mL)followed by ethanol (250 μL) and tripotassium phosphate (2 M aq, 51.3μL, 0.103 mmol). N₂ was sparged through the reaction mixture for 5 minbefore the vial was sealed and heated at 120° C. in the microwave for 30min. The solution was then filtered over a pad of Celite/MgSO₄ beforebeing concentrated in vacuo. This crude residue was purified by columnchromatography (ISCO, 12 g silica gel column, gradient of 0 to 100%EtOAc in hexanes) to give Intermediate 71a (25 mg, 0.034 mmol, 83%yield) as an off-white solid. LC-MS (Method A2) RT=1.22 min, MS (ESI)m/z: 732.3 (M+H)⁺.

Example 71

To a flask containing Intermediate 71a (25 mg, 0.034 mmol) was added THF(2 mL). Palladium on carbon (Degussa, 3.63 mg, 3.42 mol) was added andthe resulting suspension was sparged with hydrogen. The reaction mixturewas stirred vigorously under a balloon atmosphere of hydrogen. After 6h, ethanol (1 mL) was added. After 18 hours, the reaction mixture wasdiluted with EtOAc and filtered over Celite. The resulting solution wasconcentrated in vacuo then dissolved in DCM (2 mL). Triethylsilane(0.027 mL, 0.171 mmol) was added, followed TFA (0.079 mL, 1.02 mmol).After 5 min, the reaction mixture was concentrated in vacuo and purifiedvia preparative LC-MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase

A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with10 mM NH₄OAc; Gradient: 10-80% B over 20 minutes, then a 5-minute holdat 100% B; Flow: 20 mL/min to give Example 71 (5.7 mg, 0.012 mmol, 34%).LC-MS (Method A2) RT=0.96 min, MS (ESI) m/z: 492.4 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 7.53 (d, J=7.8 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.30 (s,1H), 7.03 (s, 4H), 6.95 (s, 1H), 5.44 (s, 2H), 2.76 (q, J=7.3 Hz, 2H),2.61 (t, J=11.4 Hz, 1H), 2.55 (s, 6H), 1.81 (t, J=14.9 Hz, 4H), 1.70 (d,J=11.9 Hz, 1H), 1.55-1.42 (m, 2H), 1.37 (q, J=12.4 Hz, 2H), 1.24 (m, 4H)(1 exchangeable proton not observed).

Example 72:3-(4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-1,2,4-oxadiazole-5(4H)-thione

Intermediate 72a:4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

To a solution of Intermediate 001d (120 mg, 0.307 mmol) and3-bromo-[1,1′-biphenyl]-4-carbonitrile (103 mg, 0.399 mmol) in1,4-dioxane (3 mL) was added tripotassium phosphate (2 M aq, 0.460 mL,0.920 mmol) followed by PdCl₂(dppf) (22.4 mg, 0.031 mmol). The resultingmixture was sparged with N₂ for 2 min before being sealed and heated at120° C. for 45 min in the microwave. The reaction mixture was dilutedwith EtOAc and filtered through celite. The filtrate was concentrated invacuo. The crude material was purified by column chromatography (ISCO,24 g silica gel column, 30 minute gradient of 0 to 100% EtOAc inhexanes) to give Intermediate 72a (130 mg, 0.294 mmol, 96%). LC-MS(Method A2) RT=0.93 min, MS (ESI) m/z: 443.1 (M+H)⁺. NMR (400 MHz,CDCl₃) δ 7.81 (d, J=7.9 Hz, 1H), 7.69-7.58 (m, 4H), 7.54 (d, J=8.4 Hz,2H), 7.50-7.39 (m, 3H), 7.28-7.22 (m, 2H), 6.91 (s, 1H), 5.54 (s, 2H),2.84 (q, J=7.5 Hz, 2H), 2.64 (s, 3H), 2.60 (s, 3H), 1.37-1.31 (m, 3H).

Intermediate 72b:(Z)-4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N′-hydroxy-[1,1′:3′,1″-terphenyl]-4′-carboximidamide

To a vial containing hydroxylamine hydrochloride (56.5 mg, 0.813 mmol)and potassium hydroxide (38.0 mg, 0.678 mmol) was added ethanol (678μL). The mixture was stirred vigorously for 15 min, then the suspensionwas added directly to a vial containing Intermediate 72a (30 mg, 0.068mmol) in its own solution of ethanol (678 μL). The vial was sealed andheated at 85° C. After 16 h of heating, another 5 equiv of hydroxylamine(24 mg) was added and heating was resumed for an additional 4 h. Thereaction mixture was diluted with EtOAc and washed with sat. NH₄Cl. Theorganic phase was dried over MgSO₄ and filtered over celite with anEtOAc rinse. The organic phase was concentrated in vacuo and was useddirectly in the subsequent reaction as Intermediate 72b (15 mg, 0.032mmol). LC-MS (Method A2) RT=0.72 min, MS (ESI) m/z: 476.1 (M+H)⁺.

Example 72

To a solution of Intermediate 72b (15 mg, 0.032 mmol) in DMF (2 mL) wasadded DBU (0.024 mL, 0.158 mmol) followed by1,1′-thiocarbonyldiimidazole (28.1 mg, 0.158 mmol). After 5 min, thereaction mixture was quenched with a few drops of H₂O, filtered andpurified via preparative LC-MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂Owith 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc;Gradient: 20-60% B over 20 minutes, then a 3-minute hold at 100% B;Flow: 20 mL/min to give Example 72 (7.8 mg, 0.015 mmol, 46%). LC-MS(Method A2) RT=0.95 min, MS (ESI) m/z: 518.3 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.80-7.58 (m, 4H), 7.55-7.35 (m, 3H), 7.33-6.92 (m, 6H), 5.50(br. s., 2H), 2.82 (q, J=7.0 Hz, 2H), 2.55 (s, 6H), 1.26 (t, J=7.2 Hz,3H) (1 exchangeable proton not observed).

Example 73:2-ethyl-5,7-dimethyl-3-((5′-(tetrahydrofuran-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 73a:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(tetrahydrofuran-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 55a (100 mg, 0.225 mmol), tetrahydrofuran-2-carboxylic acid(78 mg, 0.674 mmol), [IR(DFCF₃PPY)₂(BPY)]PF₆ (2.27 mg, 2.24 μmol),nickel(II) chloride ethylene glycol dimethyl ether complex (9.87 mg,0.045 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl (18.1 mg, 0.067 mmol),and cesium carbonate (219 mg, 0.674 mmol) were dissolved in DMF (4.49mL). The reaction was degassed by bubbling with N₂ for 20 minutes, thenirradiated with a 34 W Blue LED lamp. After 18 hours, the reaction wasdiluted with EtOAc and washed with saturated NaHCO₃, H₂O, then brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The crude materialwas purified by column chromatography (ISCO, 40 g silica gel column, 19minute gradient of 0 to 100% EtOAc in DCM) to give Intermediate 73a(42.3 mg, 0.097 mmol, 43%). LC-MS (Method A2) RT=0.82 min, MS (ESI) m/z:437.7 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.73 (d, J=8.0 Hz, 1H), 7.51 (d,J=8.3 Hz, 2H), 7.45 (s, 1H), 7.41 (dd, J=8.0, 1.1 Hz, 1H), 7.26 (br d,J=8.3 Hz, 2H), 6.93 (s, 1H), 5.55 (s, 2H), 4.97 (t, J=7.3 Hz, 1H),4.23-4.05 (m, J=19.5, 7.7 Hz, 1H), 4.05-3.95 (m, 1H), 2.90-2.79 (m, 2H),2.67 (s, 3H), 2.65-2.61 (m, 3H), 2.45-2.38 (m, 1H), 2.12-1.99 (m, 2H),1.79 (br dd, J=12.2, 7.8 Hz, 1H), 1.42-1.34 (m, 3H).

Intermediate 73b & Intermediate 73c:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(tetrahydrofuran-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 73a (42.3 mg, 0.097 mmol) was separated by chiral SFC(Regis Whelk-01, 21×250 mm, 5 micron column; 20% MeOH/80% CO₂ mobilephase; 45 mL/min, 150 bar, 40° C.) to give two peaks, the first elutingof which was Intermediate 73b (9.2 mg, 0.021 mmol, 22%) as a clearglassy solid. The second eluting isomer was Intermediate 73c (11.6 mg,0.027 mmol, 27%) as a clear glassy solid.

Example 73

Intermediate 73b (9 mg, 0.021 mmol) was reacted with dibutyltin oxide(5.1 mg, 0.021 mmol) and TMS-N₃ (27.4 μL, 0.206 mmol) in a manneranalogous to Example 62 to give Example 73 (1.7 mg, 0.0034 mmol, 17%).LC-MS (Method A2) RT=0.73 min, MS (ESI) m/z: 480.4 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 7.56 (br d, J=7.9 Hz, 1H), 7.44 (br d, J=7.3 Hz, 1H),7.35 (s, 1H), 7.02 (s, 4H), 6.96 (s, 1H), 5.43 (s, 2H), 4.90 (br t,J=7.2 Hz, 1H), 3.98 (q, J=7.1 Hz, 1H), 2.75 (q, J=7.4 Hz, 2H), 2.55 (s,6H), 2.35 (br dd, J=12.2, 6.4 Hz, 1H), 2.00-1.84 (m, 2H), 1.79-1.62 (m,1H), 1.28-1.13 (m, 3H), 1.00 (d, J=6.4 Hz, 1H) (1 exchangeable protonnot observed).

Example 74:2-ethyl-5,7-dimethyl-3-((5′-(tetrahydrofuran-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 73c (9 mg, 0.021 mmol) was reacted with dibutyltin oxide(6.3 mg, 0.025 mmol) and TMS-N₃ (33.4 μL, 0.252 mmol) in a manneranalogous to Example 62 to give Example 74 (5.9 mg, 0.012 mmol, 47%).LC-MS (Method A2) RT=0.73 min, MS (ESI) m/z: 480.4 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 7.56 (br d, J=7.9 Hz, 1H), 7.44 (br d, J=7.3 Hz, 1H),7.35 (s, 1H), 7.02 (s, 4H), 6.96 (s, 1H), 5.43 (s, 2H), 4.90 (br t,J=7.2 Hz, 1H), 3.98 (q, J=7.1 Hz, 1H), 2.75 (q, J=7.4 Hz, 2H), 2.55 (s,6H), 2.35 (br dd, J=12.2, 6.4 Hz, 1H), 2.00-1.84 (m, 2H), 1.79-1.62 (m,1H), 1.28-1.13 (m, 3H), 1.00 (d, J=6.4 Hz, 1H) (1 exchangeable protonnot observed).

Example 75:2-ethyl-5,7-dimethyl-3-((5′-(piperidin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 75a: tert-butyl2-(6-cyano-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-3-yl)piperidine-1-carboxylate

Intermediate 55a (150 mg, 0.337 mmol) was reacted with Boc-L-pipecolicacid (232 mg, 1.01 mmol) in a manner analogous to Intermediate 73a togive Intermediate 75a (195.2 mg, 0.355 mmol). LC-MS (Method A2) RT=0.94min, MS (ESI) m/z: 550.8 (M+H)⁺.

Intermediate 75b & Intermediate 75c: tert-butyl2-(6-cyano-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-3-yl)piperidine-1-carboxylate

Intermediate 75a (317.4 mg, 0.577 mmol) was separated by chiral SFC(Regis Whelk-01, 30×250 mm, 5 micron column; 30% MeOH/70% CO₂ mobilephase; 85 mL/min, 150 bar, 40° C.) to give two peaks, the first elutingof which was Intermediate 75b (72.4 mg, 0.132 mmol, 23%) as a clearglassy solid. The second eluting isomer was

Intermediate 75c (80.2 mg, 0.146 mmol, 25%) as a clear glassy solid.Analytical data for both enantiomers: LC-MS (Method A2) RT=0.94 min, MS(ESI) m/z: 550.8 (M+H)⁺. NMR (500 MHz, CDCl₃) δ 7.74 (d, J=8.5 Hz, 1H),7.49 (d, J=8.3 Hz, 2H), 7.33-7.30 (m, 2H), 7.26 (d, J=8.3 Hz, 2H), 6.93(s, 1H), 5.55 (s, 2H), 5.45 (br d, J=2.2 Hz, 1H), 4.08 (br d, J=14.6 Hz,1H), 2.86 (q, J=7.4 Hz, 2H), 2.77 (td, J=12.9, 3.6 Hz, 1H), 2.67 (s,3H), 2.62 (s, 3H), 2.28 (br d, J=12.9 Hz, 1H), 2.02-1.91 (m, 1H),1.70-1.60 (m, 4H), 1.46 (s, 9H), 1.37 (t, J=7.4 Hz, 3H).

Intermediate 75d:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(piperidin-2-yl)-[1,1′-biphenyl]-2-carbonitrile,2 TFA

Intermediate 75b (70 mg, 0.127 mmol) was dissolved in DCM (1.27 mL) andTFA (98 μL, 1.27 mmol). After 18 hours, the reaction was concentrated invacuo to give Intermediate 75d. LC-MS (Method A2) RT=0.61 min, MS (ESI)m/z: 450.4 (M+H)⁺.

Example 75

Intermediate 75d (10 mg, 0.022 mmol) was reacted with dibutyltin oxide(5.5 mg, 0.022 mmol) and TMS-N₃ (29.5 μL, 0.222 mmol) in a manneranalogous to Example 62 to give Example 75 (3.6 mg, 0.007 mmol, 32%).LC-MS (Method A2) RT=0.57 min, MS (ESI) m/z: 493.3 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 7.95 (s, 1H), 7.56 (br d, J=8.2 Hz, 1H), 7.40 (br s,2H), 7.06 (br d, J=8.2 Hz, 2H), 7.00-6.91 (m, 3H), 5.43 (s, 2H), 4.18(br d, J=11.9 Hz, 1H), 3.05-2.95 (m, 1H), 2.78 (q, J=7.6 Hz, 2H), 2.55(s, 6H), 1.97 (br d, J=12.2 Hz, 1H), 1.89-1.74 (m, 3H), 1.70-1.55 (m,2H), 1.25 (t, J=7.5 Hz, 3H) (2 exchangeable protons not observed).

Example 76:2-ethyl-5,7-dimethyl-3-((5′-(piperidin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 76a:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(piperidin-2-yl)-[1,1′-biphenyl]-2-carbonitrile,2 TFA

Intermediate 75c (80 mg, 0.146 mmol) was reacted in a manner analogousto Intermediate 75d to give Intermediate 76a. LC-MS (Method A2) RT=0.61min, MS (ESI) m/z: 450.4 (M+H)⁺.

Example 76

Intermediate 76a (10 mg, 0.022 mmol) was reacted with dibutyltin oxide(5.5 mg, 0.022 mmol) and TMS-N₃ (29.5 μL, 0.222 mmol) in a manneranalogous to Example 62 to give Example 76 (3.6 mg, 0.007 mmol, 32%).LC-MS (Method A2) RT=0.57 min, MS (ESI) m/z: 493.3 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 7.59 (d, J=7.8 Hz, 1H), 7.49-7.36 (m, 2H), 7.07 (br d,J=8.1 Hz, 2H), 6.99 (br d, J=8.2 Hz, 2H), 6.94 (s, 1H), 5.42 (s, 2H),3.58-3.27 (m, 3H), 2.77 (q, J=7.5 Hz, 3H), 2.55 (s, 6H), 2.09-1.60 (m,6H), 1.24 (t, J=7.5 Hz, 3H) (1 exchangeable proton not observed).

Example 77:3-((5′-(3,4-dihydro-2H-pyrrol-5-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 77a: tert-butyl2-(6-cyano-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-3-yl)pyrrolidine-1-carboxylate

Intermediate 55a (150 mg, 0.337 mmol) was reacted with1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (217 mg, 1.01 mmol)in a manner analogous to Intermediate 73a to give Intermediate 77a (66.3mg, 0.124 mmol). LC-MS (Method A2) RT=0.88 min, MS (ESI) m/z: 536.8(M+H)⁺.

Intermediate 77b: tert-butyl2-(6-cyano-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-3-yl)pyrrolidine-1-carboxylate

Intermediate 77a (289.3 mg, 0.541 mmol) was separated by chiral SFC(Regis Whelk-01, 30×250 mm, 5 micron column; 30% MeOH/70% CO₂ mobilephase; 85 mL/min, 150 bar, 40° C.) to give two peaks, the first elutingof which was Intermediate 77b (122.1 mg, 0.228 mmol, 42%) as a clearglassy solid. LC-MS (Method A2) RT=0.89 min, MS (ESI) m/z: 536.5 (M+H)⁺.¹H NMR (500 MHz, CDCl₃) δ 7.71 (d, J=8.3 Hz, 1H), 7.51-7.44 (m, 2H),7.28-7.23 (m, 4H), 6.93 (s, 1H), 5.55 (s, 2H), 5.03-4.77 (m, 1H),3.72-3.54 (m, 2H), 2.85 (q, J=7.6 Hz, 2H), 2.67 (s, 3H), 2.63 (s, 3H),2.44-2.34 (m, 1H), 1.97-1.78 (m, 3H), 1.58 (s, 9H), 1.37 (t, J=7.6 Hz,3H).

Intermediate 77c:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(pyrrolidin-2-yl)-[1,1′-biphenyl]-2-carbonitrile,2 TFA

Intermediate 77b (110 mg, 0.205 mmol) was reacted in a manner analogousto Intermediate 75d to give Intermediate 77c. LC-MS (Method A2) RT=0.59min, MS (ESI) m/z: 436.3 (M+H)⁺.

Example 77

Intermediate 77b (13 mg, 0.030 mmol) was reacted with dibutyltin oxide(7.4 mg, 0.030 mmol) and TMS-N₃ (39.6 μL, 0.298 mmol) in a manneranalogous to Example 62 with concomitant partial oxidation to giveExample 77 (3.7 mg, 0.008 mmol, 26%). LC-MS (Method A1) RT=1.20 min, MS(ESI) m/z: 477.0 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (br d, J=7.6Hz, 1H), 7.83 (s, 1H), 7.72 (br d, J=7.6 Hz, 1H), 7.13-6.99 (m, 4H),6.95 (s, 1H), 5.45 (s, 2H), 4.04-3.93 (m, 2H), 2.98 (br t, J=7.8 Hz,2H), 2.77 (q, J=7.0 Hz, 2H), 2.55 (s, 6H), 2.03-1.93 (m, 2H), 1.23 (brt, J=7.3 Hz, 3H) (1 exchangeable proton not observed).

Example 78:2-ethyl-5,7-dimethyl-3-((5′-(tetrahydro-2H-pyran-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 78a:5-(3,4-dihydro-2H-pyran-6-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 055a (215 mg, 0.536 mmol),2-(3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(338 mg, 1.61 mmol), and 2nd Generation XPHOS Precatalyst (42.2 mg,0.054 mmol) were dissolved in toluene (4.29 mL), ethanol (1.07 mL), andtripotassium phosphate (536 μL, 1.07 mmol). The reaction was degassedwith Na for 10 minutes and heated at 100° C. After 3 hours, the reactionwas diluted with EtOAc, filtered through celite/Na₂SO₄ and concentratedin vacuo. The crude material was purified by column chromatography(ISCO, 40 g silica gel column, 19 minute gradient of 0 to 100% EtOAc inhexanes) to give Intermediate 78a (182.8 mg, 0.408 mmol, 76%). LC-MS(Method A2) RT=0.91 min, MS (ESI) m/z: 449.2 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.75-7.57 (m, 3H), 7.51 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.3 Hz,2H), 6.94 (s, 1H), 5.62-5.50 (m, 3H), 4.25-4.15 (m, 2H), 2.86 (q, J=7.5Hz, 2H), 2.67 (s, 3H), 2.63 (s, 3H), 2.32-2.23 (m, 2H), 2.00-1.90 (m,2H), 1.37 (t, J=7.6 Hz, 3H).

Intermediate 78b:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(tetrahydro-2H-pyran-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 78a (180 mg, 0.401 mmol) and palladium on carbon (42.7 mg,0.040 mmol) were dissolved in MeOH (8.03 μL). The reaction was purgedwith hydrogen (0.809 mg, 0.401 mmol). After 1 hour, the reaction wasfiltered through celite and concentrated in vacuo to give Intermediate78b (180.3 mg, 0.400 mmol, 100%). LC-MS (Method A2) RT=0.89 min, MS(ESI) m/z: 451.3 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.73 (d, J=7.7 Hz,1H), 7.55-7.46 (m, 3H), 7.42 (d, J=8.0 Hz, 1H), 7.26 (br d, J=8.0 Hz,2H), 6.95 (s, 1H), 5.56 (s, 2H), 4.46-4.37 (m, 1H), 4.22-4.13 (m, 1H),3.68-3.58 (m, 1H), 2.94-2.84 (m, 2H), 2.68 (s, 3H), 2.63 (s, 3H), 1.98(br dd, J=4.1, 2.2 Hz, 1H), 1.89 (br d, J=13.2 Hz, 1H), 1.75-1.64 (m,4H), 1.37 (t, J=7.6 Hz, 3H).

Intermediate 78c:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(tetrahydro-2H-pyran-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 78b (180 mg, 0.399 mmol) was separated by chiral SFC(Chiralcel OJ-H, 21×250 mm, 5 micron column; 20% MeOH/80% CO₂ mobilephase; 45 mL/min, 120 bar, 40° C.) to give two peaks, the first elutingof which was Intermediate 78c (65.9 mg, 0.146 mmol, 37%)

Example 78

Intermediate 78c (65.9 mg, 0.146 mmol) was reacted with dibutyltin oxide(72.8 mg, 0.293 mmol) and TMS-N₃ (97 μL, 0.731 mmol) in a manneranalogous to Example 62 to give Example 78 (63.7 mg, 0.129 mmol, 85%).LC-MS (Method A2) RT=0.81 min, MS (ESI) m/z: 494.3 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 7.59 (br d, J=7.9 Hz, 1H), 7.49 (br d, J=7.9 Hz, 1H),7.42 (s, 1H), 7.04 (s, 4H), 6.96 (s, 1H), 5.45 (s, 2H), 4.45 (br d,J=11.1 Hz, 1H), 4.04 (br d, J=11.2 Hz, 1H), 3.17 (br d, J=3.3 Hz, 1H),2.78-2.73 (m, 2H), 2.51 (s, 6H), 1.93-1.84 (m, 2H), 1.56 (br s, 2H),1.50-1.42 (m, 1H), 1.21 (br t, J=7.4 Hz, 3H) (1 exchangeable proton notobserved).

Example 79:2-ethyl-5,7-dimethyl-3-((5′-(tetrahydro-2H-pyran-3-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Example 79 was prepared in a manner analogous to Example 78. LC-MS(Method A2) RT=0.75 min, MS (ESI) m/z: 494.2 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.52 (br d, J=7.7 Hz, 1H), 7.34 (br d, J=7.6 Hz, 1H), 7.26(s, 1H), 7.09-7.04 (m, 2H), 7.03-6.98 (m, 2H), 6.94 (s, 1H), 5.43 (s,2H), 3.92-3.83 (m, 2H), 3.42 (br t, J=10.7 Hz, 1H), 2.87 (br t, J=10.9Hz, 1H), 2.78 (q, J=7.4 Hz, 2H), 2.58-2.49 (m, 6H), 1.99 (br d, J=12.5Hz, 1H), 1.85-1.74 (m, 1H), 1.67 (br d, J=3.4 Hz, 2H), 1.26 (t, J=7.4Hz, 4H) (1 exchangeable proton not observed).

Example 80:3-((5′-cyclopentyl-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 80a:5-cyclopentyl-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 55a (50 mg, 0.112 mmol), bromocyclopentane (18.8 μL, 0.168mmol), [IR(DFCF₃PPY)₂(BPY)]PF₆ (1.13 mg, 1.12 μmol),Tris(trimethylsilyl)silane (34.6 μL, 0.112 mmol), Na₂CO₃ (23.8 mg, 0.225mmol), nickel chloride dimethoxyethane adduct (2.47 mg, 0.011 mmol), and4,4′-di-tert-butyl-2,2′-dipyridyl (3.01 mg, 0.011 mmol) were dissolvedin DME (2.24 mL). The solution was degassed with N₂ for 10 min. Themixture was then sealed and irradiated with a 34W Blue LED lamp. After18 hours, the reaction was diluted with EtOAc, filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 12 g silica gel column, 17 minute gradient of 0 to100% EtOAc in DCM) to give Intermediate 80a (58.6 mg, 0.135 mmol), whichwas contaminated with des-bromo product and was used directly in thesubsequent reaction. LC-MS (Method A2) RT=0.99 min, MS (ESI) m/z: 435.2(M+H)⁺.

Example 80

Intermediate 80a (58.6 mg, 0.135 mmol) was reacted with dibutyltin oxide(67.1 mg, 0.270 mmol) and TMS-N₃ (89 μL, 0.674 mmol) in a manneranalogous to Example 62 to give Example 80 (8.8 mg, 0.018 mmol, 13%).LC-MS (Method A2) RT=0.88 min, MS (ESI) m/z: 478.2 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 7.62-7.51 (m, 1H), 7.45 (br s, 1H), 7.35 (br s, 1H),7.05 (br s, 4H), 6.97 (s, 1H), 5.45 (s, 2H), 3.09 (br t, J=8.2 Hz, 1H),2.76 (br d, J=5.2 Hz, 2H), 2.62-2.48 (m, 6H), 2.06 (br s, 2H), 1.78 (brs, 2H), 1.71-1.55 (m, 4H), 1.22 (br s, 3H) (1 exchangeable proton notobserved).

Example 81:3-((5′-cycloheptyl-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Example 81 was prepared in a manner analogous to Example 80. LC-MS(Method A2) RT=0.96 min, MS (ESI) m/z: 506.2 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.53 (br d, J=7.9 Hz, 1H), 7.38 (br d, J=7.6 Hz, 1H), 7.30(s, 1H), 7.04 (s, 4H), 6.96 (s, 1H), 5.45 (s, 2H), 2.77 (q, J=7.4 Hz,3H), 2.56 (s, 6H), 1.86 (br s, 2H), 1.81-1.63 (m, 6H), 1.62-1.49 (m,4H), 1.23 (br t, J=7.5 Hz, 3H) (1 exchangeable proton not observed).

Example 82:3-((5′-(4,4-difluoropiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 82a:5-chloro-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

To a microwave vial containing PdCl₂(dppf) (0.224 g, 0.307 mmol),Intermediate 001d (1.200 g, 3.07 mmol) and 4-chloro-2-iodobenzonitrile(1.050 g, 3.99 mmol) was added toluene (12.27 ml) followed by ethanol(3.07 ml) and K₃PO₄ (2 M, aq.) (3.07 ml, 6.13 mmol). N₂ was spargedthrough the reaction mixture for 5 min before the vial was sealed andheated at 110° C. overnight. The reaction mixture was diluted with EtOAcand washed with saturated aqueous NaHCO₃. The organic phase wasconcentrated and purified by ISCO (0-100% EtOAc/Hex) to affordIntermediate 82a (0.852 g, 2.125 mmol, 69.3% yield) as a yellow oil.LC-MS (Method A2) RT=0.83 min, MS (ESI) 401.4 (M+H)⁺. ¹H NMR (400 MHz,CDCl₃) δ 7.70 (d, J=8.4 Hz, 1H), 7.52-7.42 (m, 4H), 7.26 (s, 2H), 6.93(s, 1H), 5.55 (s, 2H), 2.84 (q, J=7.5 Hz, 2H), 2.67 (s, 3H), 2.62 (s,3H), 1.36 (t, J=7.5 Hz, 3H).

Intermediate 82b:5-(4,4-difluoropiperidin-1-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

To a vial containing Intermediate 82a (0.050 g, 0.125 mmol) was added2nd generation RuPhos precatalyst (9.69 mg, 0.012 mmol) followed sodiumt-butoxide (0.072 g, 0.748 mmol). THF (3 mL) was then added followed by4,4-difluoropiperidine (0.015 g, 0.125 mmol). The reaction vial wassealed and heated at 65° C. overnight. Reaction was concentrated andpurified on ISCO using a 24 g column eluting with 0-100% EtOAc inhexanes to yield Intermediate 82b (0.061 g, 0.126 mmol, 100% yield).LC-MS (Method A2) RT=0.85 min, MS (ESI) m/z: 486.7 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.61 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.24 (d,J=8.4 Hz, 2H), 6.93 (s, 1H), 6.91-6.87 (m, 1H), 6.85 (d, J=2.4 Hz, 1H),5.54 (s, 2H), 3.62-3.47 (m, 4H), 2.85 (q, J=7.6 Hz, 2H), 2.67 (s, 3H),2.62 (s, 3H), 2.15-2.07 (m, 4H), 1.37 (t, J=7.5 Hz, 3H).

Example 82:3-((5′-(4,4-difluoropiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a vial containing Intermediate 82b (0.061 g, 0.126 mmol) was addeddibutyltin oxide (0.063 g, 0.251 mmol) and toluene (3 mL) followed byTMS-N₃ (0.083 mL, 0.628 mmol). The reaction mixture was sealed andheated at 100° C. behind a blast shield for 18 hours. Reaction wasdiluted with EtOAc and CAN (10% Aqueous) (0.689 g, 1.256 mmol) solutionwas added to quench remaining TMSN₃ until bubbling ceased. Layers wereseparated and the organic layer was washed with brine, dried with sodiumsulfate, and concentrated. Purified on Preparative HPLC using Solvent A:10% MeOH/90% H₂O/0.1% TFA and Solvent B 90% MeOH/10% H₂O/0.1% TFA onPhenomenex AXIA C18 30×100 mm with a 10 min gradient and 5 min hold timewith a flow rate of 40 mL/min to yield Example 82 (13.37 mg, 0.024 mmol,19.29% yield). LC-MS (Method A2) RT=0.86 min, MS (ESI) m/z: 529.4(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.49 (br d, J=8.9 Hz, 1H), 7.15 (brd, J=8.5 Hz, 1H), 7.06 (s, 4H), 6.99 (br s, 1H), 6.96 (s, 1H), 5.45 (s,2H), 2.77 (q, J=7.0 Hz, 2H), 2.55 (s, 4H), 2.51-2.49 (m, 6H), 2.09-1.98(m, 4H), 1.23 (br t, J=7.3 Hz, 3H) (1 exchangeable proton not observed).

The compounds listed in the table below were synthesized using the samemethods that were used to prepare Example 82.

LC-MS m/z Ex [M + H]⁺; RT # Structure MW (Method) ¹H NMR 83

528.612 529.2; 0.78 min (Method A2) ¹H NMR (400 MHz, CDCl₃) δ 8.13 (d, J= 8.8 Hz, 1H), 7.19 (s, 4H), 7.02 (dd, J = 8.8, 2.6 Hz, 1H), 6.91 (s,1H), 6.76 (d, J = 2.6 Hz, 1H), 5.50 (s, 2H), 3.55 (t, J = 11.3 Hz, 2H),3.41-3.34 (m, 2H), 2.87- 2.77 (m, 2H), 2.60 (d, J = 7.5 Hz, 6H),2.14-1.96 (m, 4H), 1.36 (t, J = 7.6 Hz, 3H) (1 exchangeable proton notobserved) 84

554.291 555.6; 0.90 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.95 (s,1H), 7.57 (br d, J = 7.3 Hz, 1H), 7.34 (br d, J = 8.5 Hz, 1H), 7.21 (brdd, J = 15.7, 7.5 Hz, 2H), 7.15-7.07 (m, 3H), 7.02 (br d, J = 7.6 Hz,2H), 6.95 (s, 1H), 6.81 (br t, J = 7.5 Hz, 1H), 5.45 (s, 2H), 3.76 (s,2H), 2.89 (s, 3H), 2.82-2.75 (m, 2H), 2.74 (s, 3H), 1.31 (s, 6H), 1.24(br t, J = 7.5 Hz, 3H) (1 exchangeable proton not observed) 85

542.609 543.9; 0.87 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (brd, J = 2.5 Hz, 1H), 7.78 (br d, J = 8.0 Hz, 1H), 7.72-7.61 (m, 2H), 7.54(s, 1H), 7.44 (dd, J = 9.6, 2.4 Hz, 1H), 7.16 (br d, J = 7.7 Hz, 2H),7.11-6.98 (m, 3H), 6.95 (s, 1H), 6.72 (d, J = 3.1 Hz, 1H), 5.44 (s, 2H),3.67 (br s, 6H), 2.76 (br d, J = 7.4 Hz, 2H), 1.21 (br t, Hz, 3H) (1exchangeable proton not observed) 86

506.645 507.3; 0.78 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ7.46-7.39 (m, 1H), 7.03 (br s, 5H), 6.95 (s, 1H), 6.85 (br s, 1H), 5.44(s, 2H), 3.53 (br s, 2H), 3.33-3.25 (m, 2H), 2.80-2.74 (m, 2H), 2.55 (s,6H), 2.18 (br t, J = 8.1 Hz, 2H), 1.95-1.86 (m, 2H), 1.52 (br d, J =12.8 Hz, 1H), 1.23 (s, 3H), 1.00 (d, J = 6.1 Hz, 3H) (1 exchangeableproton not observed) 87

522.644 523.6; 0.72 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.44 (d,J = 8.9 Hz, 1H), 7.09-7.02 (m, 5H), 6.95 (s, 1H), 6.88 (d, J = 2.4 Hz,1H), 5.44 (s, 2H), 3.45-3.34 (m, 1H), 3.25 (s, 3H), 3.04 (br s, 2H),2.92 (q, J = 7.2 Hz, 4H), 2.81-2.72 (m, 2H), 2.52-2.51 (m, 6H), 1.90 (brd, J = 6.7 Hz, 2H), 1.21 (t, J = 7.5 Hz, 3H) (1 exchangeable proton notobserved) 88

506.645 507.3; 0.78 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.37 (m,1H), 7.03 (br s, 5H), 6.95 (s, 1H), 6.85 (br s, 1H), 5.44 (s, 2H), 3.53(br s, 2H), 3.33-3.25 (m, 2H), 2.80- 2.74 (m, 2H), 2.53 (s, 6H), 2.18(br t, J = 8.1 Hz, 2H), 1.95-1.86 (m, 2H), 1.52 (br d, J = 12.8 Hz, 1H),1.22 (s, 3H), 1.00 (d, J = 6.1 Hz, 3H) (1 exchangeable proton notobserved) 89

492.618 493.7; 0.82 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.38 (d,J = 8.5 Hz, 1H), 7.06 (d, J = 8.1 Hz, 2H), 6.97 (br d, J = 8.1 Hz, 2H),6.95 (s, 1H), 6.56 (dd, J = 8.5, 2.1 Hz, 1H), 6.39 (d, J = 2.1 Hz, 1H),5.43 (s, 2H), 3.91 (s, 1H), 3.28 (br d, J = 8.5 Hz, 1H), 2.93-2.69 (m,4H), 2.55 (s, 6H), 2.40-2.05 (m, 2H), 1.59 (br dd, J = 11.9, 8.5 Hz,1H), 1.26 (t, J = 7.4 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H) (1 exchangeableproton not observed) 90

474.572 475.3; 0.77 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ7.78-7.68 (m, 2H), 7.64 (d, J = 1.5 Hz, 1H), 7.54 (br s, 2H), 7.14 (brd, J = 7.9 Hz, 2H), 7.07 (br d, J = 7.9 Hz, 2H), 6.96 (s, 1H), 6.30 (s,2H), 5.46 (s, 2H), 2.78 (q, J = 7.3 Hz, 2H), 2.55-2.54 (m, 3H),2.51-2.50 (m, 3H), 1.24 (br d, J = 3.4 Hz, 3H) (1 exchangeable protonnot observed) 91

492.631 493.2; 0.73 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.42 (brd, J = 5.3 Hz, 1H), 7.03 (br d, J = 12.1 Hz, 5H), 6.95 (s, 1H), 6.84 (brs, 1H), 5.43 (s, 2H), 3.27 (br s, 2H), 2.77 (q, J = 7.4 Hz, 2H), 2.55(s, 3H), 2.53-2.52 (m, 3H), 1.91 (s, 2H), 1.57 (br s, 6H), 1.23 (br t, J= 7.4 Hz, 3H) (1 exchangeable proton not observed) 92

534.668 535.2; 0.75 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.44 (d,J = 8.5 Hz, 1H), 7.06 (s, 4H), 6.96 (s, 1H), 6.66 (br d, J = 8.5 Hz,1H), 6.50 (s, 1H), 5.46 (s, 2H), 3.82 (t, J = 7.2 Hz, 2H), 3.59 (s, 2H),2.78 (q, J = 7.3 Hz, 2H), 2.55 (s, 6H), 2.50-2.47 (m, 2H), 2.05-1.97 (m,2H), 1.94-1.87 (m, 2H), 1.25 (t, J = 7.5 Hz, 5H) (1 exchangeable protonnot observed)

Example 93:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-phenyl-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-amine

Aniline (0.012 g, 0.123 mmol), BrettPhos 3rd generation precatalyst(7.44 mg, 8.21 μmol), and sodium t-butoxide (15.78 mg, 0.164 mmol) werecharged to a reaction flask. Intermediate 001j (0.030 g, 0.041 mmol) wasdissolved in THF (0.8 mL) and added to the reaction. The flask wasevacuated and backfilled with N₂ and stirred at 65° C. for 1 h. Thecrude reaction was passed through 0.45 μm syringe filters andconcentrated. The crude residue was dissolved in CH₂Cl₂ (1.0 mL).Triethylsilane (0.030 mL, 0.185 mmol) and TFA (0.089 mL, 1.150 mmol)were added, and the resulting mixture stirred for 1 h. The solution wasconcentrated and dissolved in 1.8 mL DMF. The crude material waspurified via preparative LC-MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂Owith 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc;Gradient: 20-100% B over 20 minutes, then a 2-minute hold at 100% B;Flow: 20 mL/min to yield Example 93 (0.007 g, 0.014 mmol, 34%): LC-MS(Method A1) RT=1.54 min, MS (ESI) m/z: 501.0 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.58 (s, 1H), 7.47 (br d, J=8.2 Hz, 1H), 7.33-7.27 (m, 2H),7.20-7.13 (m, 3H), 7.09-7.00 (m, 5H), 6.96-6.90 (m, 2H), 5.44 (s, 2H),3.47 (br s, 1H), 2.76 (q, J=7.3 Hz, 2H), 2.51 (br s, 6H), 1.21 (br t,J=7.3 Hz, 3H).

Example 94:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-methyl-N-phenyl-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-amine

Synthesized in an analogous manner to Example 93 using Intermediate 001j(0.030 g, 0.041 mmol) and N-methylaniline (0.013 g, 0.123 mmol) to yieldExample 94 (0.0023 g, 0.0045 mmol, 11%): LC-MS (Method A1) RT=1.77 min,MS (ESI) m/z: 515.0 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.46-7.36 (m,3H), 7.23 (br d, J=7.6 Hz, 2H), 7.15 (br t, J=7.2 Hz, 1H), 6.97 (br d,J=17.4 Hz, 5H), 6.90 (br d, J=7.9 Hz, 1H), 6.77 (br s, 1H), 5.41 (br s,2H), 3.31 (s, 3H), 2.73 (br d, J=7.0 Hz, 2H), 2.49 (br d, J=4.9 Hz, 6H),1.18 (br t, J=7.2 Hz, 3H) (1 exchangeable proton not observed).

Example 95:3-((5′-(azepan-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Synthesized in an analogous manner to Example 93 using Intermediate 001j(0.030 g, 0.041 mmol) and azepane (0.012 g, 0.123 mmol) to yield Example95 (0.0015 g, 0.0030 mmol, 5.9%): LC-MS (Method A1) RT=1.74 min, MS(ESI) m/z: 507.0 (M+H)⁺. NMR (500 MHz, DMSO-d₆) δ 7.40 (d, J=8.5 Hz,1H), 7.29-7.13 (m, 1H), 7.07-7.04 (m, 3H), 6.97 (s, 1H), 6.81 (br d,J=9.2 Hz, 1H), 6.61 (s, 1H), 5.45 (s, 2H), 3.53-3.46 (m, 4H), 2.78 (q,J=7.3 Hz, 2H), 2.50-2.49 (m, 6H), 1.72 (br s, 4H), 1.47 (br s, 4H), 1.23(br t, J=7.5 Hz, 3H) (1 exchangeable proton not observed).

Example 96:2-ethyl-3-((5′-(indolin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Synthesized in an analogous manner to Example 93 using Intermediate 001j(0.025 g, 0.034 mmol), indoline (0.012 g, 0.103 mmol), and 2ndgeneration XPhos precatalyst (0.0027 g, 0.0003 mmol) to yield Example 96(0.009 g, 0.017 mmol, 50%): LC-MS (Method A2) RT=0.90 min, MS (ESI) m/z:527.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.62 (d, J=8.5 Hz, 1H), 7.41(d, J=8.5 Hz, 1H), 7.30-7.18 (m, 4H), 7.18-7.08 (m, 4H), 7.06 (s, 1H),6.81 (t, J=7.2 Hz, 1H), 5.54 (s, 2H), 4.04 (t, J=8.2 Hz, 2H), 3.13 (t,J=8.2 Hz, 2H), 2.90 (q, J=7.1 Hz, 2H), 2.55 (s, 6H), 1.24 (t, J=7.5 Hz,3H) (1 exchangeable proton not observed).

Example 97:2-ethyl-5,7-dimethyl-3-((5′-(4-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Synthesized in an analogous manner to Example 93 using Intermediate 001j(0.030 g, 0.041 mmol), 4-methylpiperidine (0.012 g, 0.123 mmol), and 3ndgeneration tBuXPhos precatalyst (0.0036 g, 0.0004 mmol) to yield Example97 (0.013 g, 0.026 mmol, 64%): LC-MS (Method A2) RT=0.88 min, MS (ESI)m/z: 507.4 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.44 (d, J=8.8 Hz, 1H),7.09-6.99 (m, 5H), 6.95 (s, 1H), 6.87 (br. s., 1H), 5.44 (s, 2H), 3.85(d, J=12.6 Hz, 2H), 2.82-2.71 (m, 4H), 2.55-2.54 (m, 6H), 1.67 (d,J=12.5 Hz, 2H), 1.55 (br. s., 1H), 1.27-1.11 (m, 5H), 0.92 (d, J=6.3 Hz,3H) (1 exchangeable proton not observed).

Example 98:3-((5′-(3,3-dimethylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

3-((5′-(3,3-dimethylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Synthesized in an analogous manner to Example 93 using Intermediate 001j(0.030 g, 0.041 mmol), 3,3-dimethylpiperidine (0.009 g, 0.082 mmol), and3nd generation tBuXPhos precatalyst (0.0036 g, 0.0004 mmol) to yieldExample 98 (0.006 g, 0.001 mmol, 25%): LC-MS (Method A2) RT=0.94 min, MS(ESI) m/z: 521.4 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.43 (br d, J=8.5Hz, 1H), 7.26 (s, 1H), 7.17-7.11 (m, 2H), 7.09-7.03 (m, 3H), 6.85 (br s,1H), 5.55 (br s, 2H), 3.24 (br s, 2H), 3.02 (br s, 2H), 2.94 (br d,J=7.3 Hz, 2H), 2.57-2.55 (m, 6H), 1.63 (br s, 2H), 1.37 (br s, 2H), 1.25(br t, J=7.2 Hz, 3H), 0.94 (s, 6H) (1 exchangeable proton not observed).

Example 99:2-butyl-3-((5′-(phenylamino)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 99a:4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-chloro-[1,1′-biphenyl]-2-carbonitrile

To a microwave vial containing PdCl₂(dppf) (0.196 g, 0.268 mmol),Intermediate 033a (1.1 g, 2.68 mmol) and 4-chloro-2-iodobenzonitrile(0.918 g, 3.48 mmol) was added toluene (10.72 ml) followed by ethanol(2.68 ml) and K₃PO₄ (2 M, aq.) (2.68 ml, 5.36 mmol). N₂ was spargedthrough the reaction mixture for 5 min before the vial was sealed andheated at 120° C. in the microwave for 30 min. The reaction mixture wasdiluted with EtOAc and washed with saturated aqueous NaHCO₃. The organicphase was concentrated and purified by ISCO (0-100% EtOAc in hexanes) toafford Intermediate 99a (0.789 g, 1.879 mmol, 70.1% yield) as a whitesolid. LC-MS (Method A2) RT=0.95 min, MS (ESI) m/z: 420.3 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.72 (d, J=8.1 Hz, 1H), 7.59-7.51 (m, 3H), 7.46 (dd,J=8.4, 2.0 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 4.77 (s, 2H), 2.40-2.32 (m,2H), 2.09-1.95 (m, 6H), 1.86 (dd, J=7.0, 4.6 Hz, 2H), 1.61 (d, J=7.7 Hz,2H), 1.43-1.31 (m, 2H), 0.90 (t, J=7.4 Hz, 3H).

Intermediate 99b:4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(phenylamino)-[1,1′-biphenyl]-2-carbonitrile

To a vial containing Intermediate 99a (100 mg, 0.238 mmol) was added 2ndgeneration RuPhos precatalyst (18.50 mg, 0.024 mmol) followed sodiumt-butoxide (137 mg, 1.429 mmol). THF (3 mL) was then added followed byaniline (66.5 mg, 0.714 mmol). The reaction vial degassed with N₂ for 5minutes, sealed, and heated at 65° C. for 16 hours. The reaction mixturewas diluted with EtOAc, filtered over Celite, concentrated on to Celitefor dry loading and purified by ISCO (0-100% EtOAc in hexanes) to affordIntermediate 99b (95 mg, 0.199 mmol, 84% yield) as a colorless oil.LC-MS (Method A2) RT=1.07 min, MS (ESI) m/z: 477.4. ¹H NMR (400 MHz,CDCl₃) δ 7.62-7.57 (m, 1H), 7.56-7.50 (m, 2H), 7.43-7.35 (m, 2H), 7.26(s, 2H), 7.21 (dd, J=8.5, 0.8 Hz, 2H), 7.15 (t, J=7.4 Hz, 1H), 7.00-6.95(m, 2H), 6.12 (s, 1H), 4.75 (s, 2H), 2.40-2.32 (m, 2H), 2.06-1.94 (m,6H), 1.89-1.81 (m, 2H), 1.62 (t, J=7.7 Hz, 2H), 1.37 (dd, J=15.0, 7.5Hz, 2H), 0.90 (t, J=7.4 Hz, 3H).

Example 99:2-butyl-3-1(5′-(phenylamino)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

To a vial containing Intermediate 99b (95 mg, 0.199 mmol) was addeddibutyltin oxide (99 mg, 0.399 mmol) and toluene (5 mL) followed byTMS-N₃ (0.265 mL, 1.993 mmol). The reaction mixture was sealed andheated at 110° C. behind a blast shield. After 16 h of heating, thereaction was cooled to RT, and MeOH was added to solubilize thesolution. The reaction was diluted with EtOAc and CAN (10% Aqueous)solution (1093 mg, 1.993 mmol) was added to quench remaining TMSN₃ untilbubbling ceased. Layers were separated and the organic layer was washedwith saturated aqueous ammonium chloride, washed with brine, dried withsodium sulfate, and concentrated. The residue was dissolved in DMF, andthe crude material was purified via preparative LC-MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5ACN: H₂O with 0.1% trifluoroacetic acid; Gradient: 20-60% B over 19minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min to yieldExample 99 (5.4 mg, 10.29 mol, 5.16% yield): LC-MS (Method A2) RT=0.98min, MS (ESI) m/z: 520.4. ¹H NMR (500 MHz, DMSO-d₆) δ 8.68 (br. s., 1H),7.48 (d, J=8.3 Hz, 1H), 7.35-7.27 (m, 2H), 7.22-7.14 (m, 3H), 7.10-7.03(m, 5H), 6.95 (t, J=7.3 Hz, 1H), 4.67 (s, 2H), 2.28 (t, J=7.5 Hz, 2H),1.91-1.76 (m, 6H), 1.66 (d, J=6.9 Hz, 2H), 1.43 (d, J=6.9 Hz, 2H),1.26-1.18 (m, 2H), 0.77 (t, J=7.3 Hz, 3H) One exchangeable proton notobserved.

The compounds listed in the table below were synthesized using the samemethods that were used to prepare Example 99.

LC-MS m/z Ex [M + H]⁺; RT # Structure MW (Method) ¹H NMR 100

525.32 526.5; 1.08 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.42 (d,J = 8.5 Hz, 1H), 7.12-7.08 (m, 2H), 7.02 (d, J = 7.9 Hz, 3H), 6.84 (s,1H), 4.66 (s, 2H), 3.81 (d, J = 12.2 Hz, 2H), 2.75 (d, J = 12.8 Hz, 2H),2.30 (t, J = 7.5 Hz, 2H), 1.88-1.78 (m, 6H), 1.72-1.63 (m, 4H), 1.55(br. s., 1H), 1.51-1.43 (m, 2H), 1.31-1.16 (m, 4H), 0.93 (d, J = 6.7 Hz,3H), 0.80 (t, J = 7.2 Hz, 3H) (1 exchangeable proton not observed) 101

539.714 540.5; 1.07 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (s,1H), 7.41 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 7.01 (d, J =7.9 Hz, 3H), 6.84 (s, 1H), 4.65 (s, 2H), 3.26 (br. s., 4H), 2.29 (t, J =7.5 Hz, 2H), 1.88-1.77 (m, 6H), 1.66 (d, J = 7.0 Hz, 2H), 1.50-1.44 (m,2H), 1.42 (br. s., 4H), 1.31-1.21 (m, 2H), 0.95 (s, 6H), 0.78 (t, J =7.2 Hz, 3H) (1 exchangeable proton not observed) 102

539.714 540.5; 1.17 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.40 (brs, 1H), 7.05 (br d, J = 15.7 Hz, 5H), 6.85 (br s, 1H), 4.66 (br s, 2H),3.56 (br s, 4H), 3.23 (br s, 2H), 2.29 (br t, J = 7.5 Hz, 2H), 1.89-1.77(m, 8H), 1.64 (br s, 4H), 1.48-1.42 (m, 2H), 0.95 (s, 6H), 0.79 (br t, J= 7.3 Hz, 3H) (1 exchangeable protons not observed) 103

511.661 512.5; 0.86 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.45 (d,J = 8.7 Hz, 1H), 7.24 (s, 2H), 7.03 (s, 2H), 6.66 (dd, J = 8.63 Hz, 2.23Hz, 1H), 6.48 (s, 1H), 4.78 (s, 2H), 3.37-2.63 (m, 3H), 2.42-2.05 (m,3H), 1.87 (d, J = 7.0 Hz, 9H), 1.56-1.46 (m, 3H), 1.35-1.23 (m, 3H),1.09 (d, J = 6.6 Hz, 3H), 0.82 (t, J = 7.4 Hz, 3H) (1 exchangeableproton not observed) 104

525.688 526.5; 0.85 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.42 (d,J = 8.7 Hz, 1H), 7.09-7.06 (m, 2H), 7.02 (d, J = 8.1 Hz, 3H), 6.84 (s,1H), 4.65 (s, 2H), 3.90-3.72 (m, 4H), 2.77-2.67 (m, 1H), 2.42 (t, J =11.5 Hz, 1H), 2.29 (t, J = 7.5 Hz, 2H), 1.88-1.77 (m, 6H), 1.66 (d, J =7.4 Hz, 4H), 1.47-1.40 (m, 2H), 1.27-1.20 (m, 2H), 1.07 (d, J = 11.9 Hz,1H), 0.90 (d, J = 6.5 Hz, 3H), 0.78 (t, J = 7.3 Hz, 3H) (1 exchangeableproton not observed) 105

543.677 544.3; 1.86 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ7.79-7.73 (m, 2H), 7.70-7.63 (m, 2H), 7.49 (s, 1H), 7.21 (d, J = 7.9 Hz,2H), 7.15 (d, J = 4.9 Hz, 1H), 7.03 (d, J = 7.9 Hz, 2H), 6.73 (d, J =2.7 Hz, 1H), 4.66 (s, 2H), 3.82-3.61 (m, 4H), 2.30 (t, J = 6.4 Hz, 2H),1.90-1.74 (m, 6H), 1.65 (br. s., 2H), 1.45 (br. s., 2H), 1.30-1.19 (m,2H), 0.77 (t, J = 7.2 Hz, 3H) (1 exchangeable proton not observed) 106

525.688 526.6; 0.85 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.44 (d,J = 8.7 Hz, 1H), 7.06 (q, J = 8.0 Hz, 5H), 6.88 (s, 1H), 4.66 (s, 2H),2.29 (t, J = 7.5 Hz, 2H), 1.88-1.78 (m, 6H), 1.66 (d, J = 7.6 Hz, 4H),1.47-1.41 (m, 2H), 1.25 (td, J = 14.6, 7.0 Hz, 8H), 1.15 (t, J = 7.3 Hz,1H), 0.85 (br. s., 3H), 0.78 (t, J = 7.3 Hz, 3H) (1 exchangeable protonnot observed) 107

573.730 574.7; 0.94 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.62 (d,J = 8.5 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H),7.23 (d, J = 7.3 Hz, 1H), 7.18 (d, J = 11.9 Hz, 2H), 7.16-7.11 (m, 2H),7.09 (d, J = 8.0 Hz, 2H), 6.86 (t, J = 7.4 Hz, 1H), 4.69 (s, 2H), 2.30(t, J = 7.5 Hz, 2H), 1.92-1.77 (m, 6H), 1.66 (br. s., 2H), 1.45 (d, J =7.3 Hz, 2H), 1.36-1.18 (m, 10H), 0.86 (t, J = 7.2 Hz, 3H) (1exchangeable proton not observed) 108

571.306 572.3; 0.96 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.55 (brd, J = 8.2 Hz, 1H), 7.33-7.28 (m, 1H), 7.20-7.13 (m, 3H), 7.10-7.02 (m,2H), 6.99 (br d, J = 7.9 Hz, 2H), 6.82- 6.66 (m, 2H), 4.66 (s, 2H), 4.05(s, 2H), 2.33 (br t, J = 7.5 Hz, 2H), 1.84 (br d, J = 8.5 Hz, 6H), 1.68(br d, J = 6.7 Hz, 2H), 1.54-1.44 (m, 2H), 1.28 (br d, J = 7.6 Hz, 2H),1.09 (br s, 1H), 1.04 (br s, 1H), 1.01 (d, J = 6.1 Hz, 2H), 0.81 (br t,J = 7.3 Hz, 3H) (1 exchangeable proton not observed)

Example 109:2-butyl-3-((5′-(6-fluoro-1H-indol-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 109a:5-bromo-4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

To a microwave vial containing PdCl₂(dppf) (0.196 g, 0.268 mmol),Intermediate 033a (1.00 g, 2.44 mmol) and 4-bromo-2-iodobenzonitrile(0.975 g, 3.17 mmol) was added toluene (9.75 ml) followed by ethanol(2.44 ml) and K₃PO₄ (2 M, aq.) (2.44 ml, 4.87 mmol). N₂ was spargedthrough the reaction mixture for 5 min before the vial was sealed andheated at 120° C. in the microwave for 30 min. The reaction mixture wasdiluted with EtOAc and washed with saturated aqueous NaHCO₃. The organicphase was concentrated and purified by ISCO (0-100% EtOAc in hexanes) toafford Intermediate 109a (0.906 g, 1.95 mmol, 80% yield) as a whitesolid. LC-MS (Method A2) RT=0.87 min, MS (ESI) m/z: 464.6 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.70-7.68 (m, 1H), 7.65-7.61 (m, 2H), 7.55 (d, J=8.4Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 4.77 (s, 2H), 2.40-2.32 (m, 2H), 2.02(br d, J=4.6 Hz, 6H), 1.86 (br s, 2H), 1.67-1.58 (m, 2H), 1.44-1.31 (m,2H), 0.90 (t, J=7.4 Hz, 3H).

Intermediate 109b:4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(6-fluoro-1H-indol-1-yl)-[1,1′-biphenyl]-2-carbonitrile

To a vial charged with Intermediate 109a (0.050 g, 0.108 mmol),6-fluoro-1H-indole (0.044 g, 0.323 mmol), copper(I) iodide (10.25 mg,0.054 mmol), potassium carbonate (0.074 g, 0.538 mmol) and L-proline(0.012 g, 0.108 mmol) was added DMSO (2.153 ml). The mixture was andheated at 120° C. for 16 hours. The reaction was diluted with EtOAc andfiltered through Celite. The filtrate was washed with H₂O×3, washed withbrine, and dried over sodium sulfate. The reaction was purified on ISCOusing 24 g column eluting with 0-100% EtOAc in hexanes to yieldIntermediate 109b (0.031 g, 0.060 mmol, 55.5% yield). LC-MS (Method A2)RT=0.96 min, MS (ESI) m/z: 519.8 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.94(s, 1H), 7.68-7.50 (m, 5H), 7.40-7.29 (m, 4H), 7.06-6.96 (m, 1H), 6.76(dd, J=3.4, 0.8 Hz, 1H), 4.79 (s, 2H), 2.45-2.29 (m, 2H), 2.07-1.95 (m,6H), 1.87 (td, J=4.3, 1.3 Hz, 2H), 1.71-1.59 (m, 2H), 1.44-1.34 (m, 2H),0.94-0.88 (m, 3H).

Example 109:2-butyl-3-((5′-(phenylamino)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 109b(0.031 g, 0.060 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 ACN: H₂O with 0.1% trifluoroacetic acid; Gradient: 30-70%B over 19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min toyield Example 109 (13.1 mg, 0.023 mmol, 39.0% yield): LC-MS (Method A2)RT=0.87 min, MS (ESI) m/z: 562.8 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ7.82 (br d, J=9.7 Hz, 3H), 7.73-7.61 (m, 2H), 7.47 (br d, J=9.5 Hz, 1H),7.20 (br d, J=7.8 Hz, 2H), 7.09 (br d, J=7.8 Hz, 2H), 7.04 (br t, J=9.0Hz, 1H), 6.78 (br d, J=3.0 Hz, 1H), 4.68 (s, 2H), 2.29 (br t, J=7.4 Hz,2H), 1.82 (br d, J=10.0 Hz, 6H), 1.67 (br d, J=7.6 Hz, 2H), 1.52 (br d,J=6.9 Hz, 2H), 1.24-1.18 (m, 2H), 0.75 (br t, J=7.2 Hz, 3H) (1exchangeable proton not observed).

Example 110:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-methyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 110a: 1-acetamidocyclopentane-1-carboxamide

To a solution of 1-aminocyclopentane-1-carboxamide (1.15 g, 8.97 mmol)and DCM (32 mL) was added acetic anhydride (1.191 g, 11.66 mmol). Thereaction mixture was stirred at RT for 18 hours. Reaction wasconcentrated and used without further purification in the next step.Intermediate 110a (1.53 g, 8.99 mmol, 100% yield). LC-MS (Method A2)RT=0.43 min, MS (ESI) m/z: 171.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ7.09-6.89 (m, 1H), 5.72 (br s, 1H), 5.38-5.19 (m, 1H), 2.40-2.30 (m,2H), 2.07-1.98 (m, 5H), 1.86-1.75 (m, 4H)

Intermediate 110b: 2-methyl-1,3-diazaspiro[4.4]non-1-en-4-one

To a solution of Intermediate 110a (1.53 g, 8.99 mmol) in MeOH (20 mL)was added 3.0 N NaOH (23.97 mL, 71.9 mmol). The reaction mixture washeated at 50° C. for 5 hours. The reaction was cooled to RT, and themixture was acidified with 1.0 N HCl to pH 6-7 and extracted with DCM.The organic layer was dried over sodium sulfate and concentrated to givecrude Intermediate 110b (0.162 g, 1.064 mmol, 11.84% yield). This wasused for the next step without purification. LC-MS (Method A2) RT=0.44min, MS (ESI) m/z: 153.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 2.25 (s, 3H),2.08 (s, 1H), 2.02-1.92 (m, 6H), 1.86-1.80 (m, 2H).

Intermediate 110c:5-bromo-4′-((2-methyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 110b (0.162 g, 1.064 mmol) was dissolved in DMF (2.129 ml).NaH (0.106 g, 2.66 mmol) was added and allowed to stir for 15 min.Intermediate I-002 (0.448 g, 1.277 mmol) was added. The reaction wasstirred for 30 min and was diluted with EtOAc. The organic layer waswashed with saturated NH₄Cl, washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The material was purified by columnchromatography (ISCO, 80 g silica gel column, 36 minute gradient of 0 to100% EtOAc in hexanes) to yield Intermediate 110c (0.310 g, 0.734 mmol,69.0% yield). LC-MS (Method A2) RT=0.84 min, MS (ESI) m/z: 422.0 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 7.61-7.59 (m, 1H), 7.54 (dd, J=2.8, 1.2 Hz,2H), 7.48-7.44 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 4.68 (s, 2H), 2.05 (s,3H), 1.99-1.87 (m, 6H), 1.76 (br dd, J=7.3, 5.3 Hz, 2H).

Intermediate 110d:4′-((2-methyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 110c (0.315 g, 0.834 mmol), bis(pinacolato)diboron (0.423g, 1.667 mmol), XPhos (0.040 g, 0.083 mmol), Pd₂(dba)₃ (0.076 g, 0.083mmol), and KOAc (0.409 g, 4.17 mmol) were dissolved in dioxane (8.34ml). The reaction was heated at 100° C. for 2 hours. The reaction wascooled to ambient temperature, diluted with EtOAc, filtered throughCelite, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 24 g silica gel column, 19 minute gradientof 0 to 100% EtOAc in DCM) to yield Intermediate 110d (0.300 g, 0.639mmol, 77%). LC-MS (Method A2) RT=0.68 min, MS (ESI) m/z: 388.1 (M+H)⁺for boronic acid. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.89-7.85 (m,1H), 7.77 (d, J=7.7 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz,2H), 5.32 (s, 2H), 2.14 (s, 3H), 2.04-1.97 (m, 6H), 1.84 (br d, J=4.0Hz, 2H), 1.29 (s, 12H).

Intermediate 110e:4″-((2-methyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

Intermediate 110d (40 mg, 0.085 mmol), bromobenzene (40.1 mg, 0.256mmol), and 2nd generation XPhos precatalyst (6.70 mg, 8.52 mol) weredissolved in toluene (1363 μl), EtOH (341 μl), and 2M tripotassiumphosphate (85 μl, 0.170 mmol) was added. The reaction was heated at 100°C. for one hour. The reaction was diluted with EtOAc, filtered throughCelite and concentrated in vacuo. The crude material will be used as-iswithout further purification for the subsequent reaction. Intermediate110e (36 mg, 0.086 mmol, 101% yield): LC-MS (Method A2) RT=0.92 min, MS(ESI) m/z: 420.1 (M+H)⁺.

Example 110:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-methyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 110e(0.040 g, 0.095 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 12-56% B over 23 minutes, then a6-minute hold at 100% B; Flow: 20 mL/min Example 110 (1.2 mg, 2.491μmol, 2.61% yield): LC-MS (Method A2) RT=0.83 min, MS (ESI) m/z: 463.2(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.78 (br d, J=7.3 Hz, 2H), 7.75-7.69(m, 2H), 7.63 (s, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.42-7.38 (m, 1H), 7.21(d, J=7.9 Hz, 2H), 7.06 (br d, J=8.2 Hz, 2H), 4.68 (s, 2H), 2.05 (s,3H), 1.88-1.79 (m, 6H), 1.69 (br d, J=7.3 Hz, 2H) (1 exchangeable protonnot observed).

Example 111:2-methyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 111a:4′-((2-methyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110e using Intermediate110d (0.040 g, 0.085 mmol) and 2-bromo-4-methylpyridine (0.044 g, 0.256mmol) to yield Intermediate 111a (0.037 g, 0.085 mmol, 100%). LC-MS(Method A2) RT=0.72 min, MS (ESI) m/z: 435.2 (M+H)⁺.

Example 111:2-methyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 111a(0.040 g, 0.092 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 ACN: H₂O with 0.1% trifluoroacetic acid; Gradient: 2-42% Bover 23 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min Example111: LC-MS (Method A2) RT=0.61 min, MS (ESI) m/z: 478.3 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.55 (d, J=4.9 Hz, 1H), 8.19 (br d, J=8.2 Hz, 1H),8.13 (s, 1H), 7.98 (s, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.24 (br d, J=4.9Hz, 1H), 7.20 (d, J=7.9 Hz, 2H), 7.10 (br d, J=7.9 Hz, 2H), 4.70 (s,2H), 2.42 (s, 3H), 2.05 (s, 3H), 1.90-1.81 (m, 6H), 1.68 (br s, 2H) (1exchangeable proton not observed).

Example 112:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 112a: 1-propionamidocyclopentane-1-carboxamide

To a solution of 1-aminocyclopentane-1-carboxamide (1.00 g, 7.80 mmol)in DCM (16 mL) was added TEA (2.72 mL, 19.50 mmol). The mixture wascooled to 0° C. with an ice bath. Propionyl chloride (1.011 g, 10.92mmol) in DCM (4 mL) was added dropwise to the stirred solution, and thereaction mixture was at RT for 18 hours. The reaction was diluted withH₂O and DCM. The organic phase was collected. The aqueous phase wasextracted (2×) with DCM. The combined organic phase was washed withbrine, dried over sodium sulfate and concentrated to give Intermediate112a (0.586 g, 3.18 mmol, 40.8% yield) as a solid. LC-MS (Method A2)RT=0.46 min, MS (ESI) m/z: 185.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ9.37-9.15 (m, 2H), 8.71 (br d, J=0.9 Hz, 1H), 2.42 (q, J=7.4 Hz, 2H),2.39-2.29 (m, 2H), 1.85-1.68 (m, 4H), 1.67-1.58 (m, 2H), 1.14-1.10 (m,3H).

Intermediate 112b: 2-ethyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 110b using Intermediate112a (0.586 g, 3.18 mmol) to yield Intermediate 112b (0.445 g, 2.68mmol, 84%). LC-MS (Method A2) RT=0.46 min, MS (ESI) m/z: 167.1 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 5.53 (br s, 1H), 2.42 (q, J=7.7 Hz, 2H), 1.82(br d, J=3.7 Hz, 2H), 1.77-1.70 (m, 6H), 1.18 (t, J=7.6 Hz, 3H).

Intermediate 112c:5-bromo-4′-((2-ethyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110c using Intermediate112b (0.176 g, 1.059 mmol) and Intermediate I-002 (0.446 g, 1.271 mmol)to yield Intermediate 112c (0.232 g, 0.532 mmol, 50%). LC-MS (Method A2)RT=0.87 min, MS (ESI) 436.0 [M+H]⁺ ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.68(m, 1H), 7.65-7.62 (m, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.6 Hz,2H), 5.32 (s, 2H), 2.43-2.36 (m, 2H), 2.06-1.95 (m, 6H), 1.90-1.85 (m,2H), 1.22 (t, J=7.5 Hz, 3H).

Intermediate 112d:4′-((2-ethyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110d using Intermediate112c (0.232 g, 0.532 mmol) to yield Intermediate 112d (0.257 g, 0.455mmol, 86%). LC-MS (Method A2) RT=0.67 min, MS (ESI) m/z: 402.1 (M+H)⁺for boronic acid. ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.85 (dd,J=7.7, 1.1 Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.56 (d, J=8.1 Hz, 2H),7.30-7.26 (m, 2H), 4.74 (s, 2H), 2.42-2.30 (m, 2H), 2.07-1.94 (m, 6H),1.90-1.79 (m, 2H), 1.37-1.26 (m, 12H), 1.19 (t, J=7.4 Hz, 3H).

Intermediate 112e:4″-((2-ethyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

Synthesized in an analogous manner to Example 110e using Intermediate112d (0.030 g, 0.069 mmol) and bromobenzene (0.029 g, 0.186 mmol) toyield Intermediate 112e (0.030 g, 0.062 mmol, 100%). LC-MS (Method A2)RT=0.90 min, MS (ESI) m/z: 434.1 (M+H)⁺.

Example 112:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 112e(0.030 g, 0.062 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 15-60% B over 19 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min Example 112 (0.0015 g, 0.00308mmol, 3.11%): LC-MS (Method A2) RT=0.81 min, MS (ESI) m/z: 477.2 (M+H)⁺.¹H NMR (500 MHz, DMSO-d₆) δ 7.90-7.87 (m, 1H), 7.83 (br d, J=7.3 Hz,2H), 7.80-7.76 (m, 2H), 7.52 (br t, J=7.6 Hz, 2H), 7.46 (br d, J=7.3 Hz,1H), 7.20 (br d, J=7.6 Hz, 2H), 7.12 (br d, J=7.6 Hz, 2H), 4.70 (s, 2H),2.34 (br d, J=7.3 Hz, 2H), 2.06-1.74 (m, 6H), 1.70 (br d, J=5.8 Hz, 2H),1.05 (t, J=7.3 Hz, 3H) (1 exchangeable proton not observed).

Example 113:2-ethyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 113a:5-(4-methypyridin-2-yl)-4′-((4-oxo-2-ethyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110e using Intermediate112d (0.030 g, 0.069 mmol) and 2-bromo-4-methylpyridine (0.032 g, 0.186mmol) to yield Intermediate 113a (0.030 g, 0.067 mmol, 100%). LC-MS(Method A2) RT=0.75 min, MS (ESI) m/z: 449.0 (M+H)⁺.

Example 113:2-ethyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 113a(0.030 g, 0.067 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 13-53% B over 20 minutes, then a4-minute hold at 100% B; Flow: 20 mL/min Example 113 (0.0041 g, 0.00782mmol, 8.3%): LC-MS (Method A2) RT=0.65 min, MS (ESI) m/z: 492.2 (M+H)⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (d, J=5.0 Hz, 1H), 8.27 (br d, J=7.9Hz, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.27 (br d,J=4.8 Hz, 1H), 7.22-7.19 (m, 2H), 7.19-7.14 (m, 2H), 4.74 (s, 2H),2.47-2.40 (m, 5H), 1.89 (br d, J=7.3 Hz, 6H), 1.81-1.69 (m, 2H), 1.09(t, J=7.4 Hz, 3H) (1 exchangeable proton not observed).

Example 114:(R)-3-((5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-propyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 114a: 1-butyramidocyclopentane-1-carboxamide

To a solution of 1-aminocyclopentane-1-carboxamide (0.500 g, 3.90 mmol)in DCM (16 mL) was added TEA (1.359 mL, 9.75 mmol). The mixture wascooled with an ice bath. Butyryl chloride (0.572 mL, 5.46 mmol) in DCM(4 mL) was added dropwise to the stirred solution, and the reactionmixture was at RT for 18 hours. The reaction was diluted with H₂O andDCM. The organic phase was collected. The aqueous phase was extracted(2×) with DCM. The combined organic phase was washed with brine, driedover sodium sulfate, and concentrated to give Intermediate 114a (0.300g, 1.513 mmol, 38.8% yield) as a solid. LC-MS (Method A2) RT=0.54 min,MS (ESI) m/z: 199.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.15-6.86 (m, 2H),5.38-5.27 (m, 1H), 2.28-2.18 (m, 2H), 2.14-2.07 (m, 2H), 1.98-1.89 (m,2H), 1.75-1.65 (m, 4H), 1.62-1.56 (m, 2H), 0.90-0.87 (m, 3H).

Intermediate 114b: 2-propyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 110b using Intermediate114a (0.307 g, 1.548 mmol) to yield Intermediate 114b (0.110 g, 0.610mmol, 39%). LC-MS (Method A2) RT=0.48 min, MS (ESI) m/z: 181.0 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 5.64-5.45 (m, 1H), 2.36 (t, J=7.4 Hz, 2H),2.20 (t, J=7.5 Hz, 2H), 2.13-1.96 (m, 2H), 1.92-1.78 (m, 2H), 1.76-1.65(m, 4H), 1.02-0.98 (m, 3H)

Intermediate 114c:5-bromo-4′-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110c using Intermediate114b (0.555 g, 3.08 mmol) and Intermediate I-002 (1.297 g, 3.69 mmol) toyield Intermediate 114c (0.668 g, 1.483 mmol, 48%). LC-MS (Method A2)RT=0.87 min, MS (ESI) m/z: 436.0 [M+H]⁺

Intermediate 114d:4′-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110d using Intermediate114c (0.450 g, 0.999 mmol) to yield Intermediate 114d (0.442 g, 0.889mmol, 89%). LC-MS (Method A2) RT=0.96 min, MS (ESI) m/z: 498.3 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.84 (d, J=1.1 Hz, 1H),7.77-7.73 (m, 1H), 7.56 (d, J=8.4 Hz, 2H), 7.28 (s, 2H), 4.74 (s, 2H),2.38-2.26 (m, 2H), 2.04-1.94 (m, 6H), 1.84 (td, J=4.8, 2.8 Hz, 2H),1.70-1.62 (m, 2H), 1.35 (s, 12H), 0.95 (t, J=7.4 Hz, 3H).

Intermediate 114e:4″-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

Synthesized in an analogous manner to Example 110e using Intermediate114d (0.030 g, 0.060 mmol) and bromobenzene (0.028 g, 0.181 mmol) toyield Intermediate 114e (0.030 g, 0.067 mmol, 100%). LC-MS (Method A2)RT=0.93 min, MS (ESI) m/z: 448.2

(M+H)⁺.

Example 114:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 114e(0.030 g, 0.060 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 17-57% B over 25 minutes, then a6-minute hold at 100% B; Flow: 20 mL/min Example 114 (0.0112 g, 0.022mmol, 23%): LC-MS (Method A2) RT=0.83 min, MS (ESI) 491.2 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 7.81-7.76 (m, 3H), 7.74-7.70 (m, 1H), 7.67 (s, 1H),7.50 (t, J=7.6 Hz, 2H), 7.44-7.39 (m, 1H), 7.19 (br d, J=7.9 Hz, 2H),7.06 (br d, J=7.9 Hz, 2H), 4.68 (s, 2H), 2.30 (t, J=7.3 Hz, 2H),1.90-1.79 (m, 6H), 1.68 (br d, J=7.6 Hz, 2H), 1.58-1.50 (m, 2H), 0.86(t, J=7.3 Hz, 3H). (1 exchangeable proton not observed).

Example 115:3-((5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-propyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 115a:5-(4-methoxypyridin-2-yl)-4′-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110e using Intermediate114d (0.030 g, 0.060 mmol) and 2-bromo-4-methoxylpyridine (0.034 g,0.181 mmol) to yield Intermediate 115a (0.030 g, 0.060 mmol, 100%).LC-MS (Method A2) RT=0.67 min, MS (ESI) m/z: 479.2 (M+H)⁺.

Example 115:3-((5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-propyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 115a(0.030 g, 0.060 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 8-48% B over 25 minutes, then a6-minute hold at 100% B; Flow: 20 mL/min. Example 115 (0.0083 g, 0.016mmol, 17.4%): LC-MS (Method A2) RT=0.59 min, MS (ESI) 522.2 (M+H)⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.49 (d, J=5.6 Hz, 1H), 8.13 (dd, J=8.0, 1.6Hz, 1H), 8.09 (d, J=1.4 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.58 (d, J=2.1Hz, 1H), 7.21 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.1 Hz, 2H), 6.96 (dd,J=5.6, 2.3 Hz, 1H), 4.68 (s, 2H), 3.94 (s, 3H), 2.32 (t, J=7.3 Hz, 2H),1.90-1.81 (m, 6H), 1.70 (br d, J=7.2 Hz, 2H), 1.63-1.53 (m, 2H), 0.89(t, J=7.4 Hz, 3H) (1 exchangeable proton not observed).

Example 116:3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-propyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 116a:5-(4-methylpyridin-2-yl)-4′-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110e using Intermediate114d (0.030 g, 0.060 mmol) and 2-bromo-4-methylpyridine (0.031 g, 0.181mmol) to yield Intermediate 116a (0.030 g, 0.060 mmol, 100%). LC-MS(Method A2) RT=0.75 min, MS (ESI) m/z: 463.2 (M+H)⁺.

Example 116:3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-propyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 116a(0.030 g, 0.060 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 12-52% B over 20 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min Example 116 (0.018 g, 0.035mmol, 38%): LC-MS (Method A2) RT=1.21 min, MS (ESI) 506.3 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.53 (d, J=4.9 Hz, 1H), 8.13-8.08 (m, 1H), 8.04 (s,1H), 7.90 (s, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.25-7.17 (m, 3H), 7.05 (d,J=7.9 Hz, 2H), 4.68 (s, 2H), 2.41 (s, 3H), 2.33 (t, J=7.3 Hz, 2H),1.92-1.83 (m, 6H), 1.70 (br d, J=6.9 Hz, 2H), 1.59 (sxt, J=7.3 Hz, 2H),0.90 (t, J=7.4 Hz, 3H) (1 exchangeable proton not observed).

Example 117:(R)-3-((5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-propyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 117a:2-propyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 110c using Intermediate114b (0.555 g, 3.08 mmol) and2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.463g, 1.558 mmol) to yield Intermediate 117a (0.214 g, 0.540 mmol, 42%).LC-MS (Method A2) RT=0.85 min, MS (ESI) m/z: 397.2 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.79 (d, J=8.1 Hz, 2H), 7.17 (d, J=8.1 Hz, 2H), 4.71 (s,2H), 2.30-2.22 (m, 2H), 2.08-1.93 (m, 6H), 1.87-1.79 (m, 2H), 1.65-1.59(m, 2H), 1.36 (s, 12H), 0.93 (t, J=7.4 Hz, 3H).

Intermediate 117b:5-chloro-4′-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

To a microwave vial containing PdCl₂(dppf) (0.036 g, 0.049 mmol),Intermediate 117a (0.194 g, 0.489 mmol) and 4-chloro-2-iodobenzonitrile(0.168 g, 0.636 mmol) was added toluene (1.958 ml) followed by ethanol(0.489 ml) and K₃PO₄ (2 M, aq.) (0.489 ml, 0.979 mmol). N₂ was spargedthrough the reaction mixture for 5 min before the vial was sealed andheated at 110° C. for 18 hours. The reaction mixture was diluted withEtOAc and washed with sat. NaHCO₃. The organic phase was concentratedand purified by ISCO (0-100% EtOAc in hexanes) to afford Intermediate117b (0.181 g, 0.446 mmol, 91% yield) as a yellow oil. LC-MS (Method A2)RT=0.80 min, MS (ESI) m/z: 406.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.72(d, J=8.1 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.52 (d, J=1.8 Hz, 1H), 7.46(dd, J=8.4, 2.2 Hz, 1H), 7.32 (d, J=8.6 Hz, 2H), 4.77 (s, 2H), 2.37-2.32(m, 2H), 2.10-1.97 (m, 6H), 1.90-1.83 (m, 2H), 1.72-1.63 (m, 2H), 0.97(t, J=7.5 Hz, 3H).

Intermediate 117c:(R)-5-(3-methylpiperidin-1-yl)-4′-((4-oxo-2-propyl-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Intermediate 99b usingIntermediate 117b (0.040 g, 0.099 mmol) and (R)-3-methylpiperidine(0.0097 g, 0.099 mmol) to yield Intermediate 117c (0.032 g, 0.069 mmol,70%). LC-MS (Method A2) RT=1.01 min, MS (ESI) m/z: 469.3 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.57 (d, J=8.8 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.26(s, 2H), 6.88-6.82 (m, 2H), 4.75 (s, 2H), 3.90-3.70 (m, 2H), 2.87 (td,J=12.3, 3.1 Hz, 1H), 2.56 (dd, J=12.7, 10.7 Hz, 1H), 2.36 (dd, J=8.3,7.2 Hz, 2H), 2.11-1.93 (m, 7H), 1.89-1.81 (m, 3H), 1.81-1.62 (m, 4H),1.23-1.11 (m, 1H), 1.03-0.91 (m, 6H).

Example 117:(R)-3-((5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-propyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 117c(0.032 g, 0.069 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 33-58% B over 25 minutes, then a2-minute hold at 100% B; Flow: 20 mL/min Example 117 (0.0049 g, 0.0093mmol, 13%): LC-MS (Method A2) RT=0.81 min, MS (ESI) 512.3 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 7.43 (br s, 1H), 7.10 (br s, 2H), 7.02 (br d, J=6.9Hz, 3H), 6.85 (br s, 1H), 4.65 (s, 2H), 3.72 (br t, J=12.0 Hz, 2H), 2.29(br t, J=7.2 Hz, 2H), 1.94-1.77 (m, 10H), 1.74-1.64 (m, 4H), 1.56 (dt,J=14.6, 7.3 Hz, 2H), 1.09 (br dd, J=11.5, 2.9 Hz, 1H), 0.93 (d, J=6.5Hz, 3H), 0.88 (t, J=7.3 Hz, 3H) (1 exchangeable proton not observed).

Example 118:2-isopropyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 118a: 1-isobutyramidocyclopentane-1-carboxamide

To a solution of 1-aminocyclopentane-1-carboxamide (1.00 g, 7.80 mmol)in DCM (16 mL) was added TEA (2.72 mL, 19.50 mmol). The mixture wascooled with an ice bath. Isobutyryl chloride (1.164 g, 10.92 mmol) inDCM (4 mL) was added dropwise to the stirred solution, and the reactionmixture was at RT for 18 hours. The reaction was diluted with H₂O andDCM. The organic phase was collected. The aqueous phase was extracted(2×) with DCM. The combined organic phase was washed with brine, driedover sodium sulfate, and concentrated to give Intermediate 118a (998 mg,5.03 mmol, 64.5% yield) as a solid. RT=0.52 min, MS (ESI) m/z: 199.1(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 5.64 (br s, 1H), 5.55 (br s, 2H),2.47-2.29 (m, 4H), 2.08-2.00 (m, 2H), 1.92-1.83 (m, 2H), 1.78-1.75 (m,1H), 1.17 (d, J=6.8 Hz, 6H).

Intermediate 118b: 2-isopropyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 110b using Intermediate118a (0.548 g, 2.76 mmol) to yield Intermediate 118b (0.448 g, 2.485mmol, 90%). LC-MS (Method A2) RT=0.44 min, MS (ESI) m/z: 181.0 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 2.76 (dt, J=14.0, 7.0 Hz, 1H), 2.01-1.88 (m,6H), 1.83 (br d, J=2.4 Hz, 2H), 1.25 (d, J=7 Hz, 6H).

Intermediate 118c:5-bromo-4′-((2-isopropyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110c using Intermediate118b (0.536 g, 2.97 mmol) and Intermediate I-002 (1.253 g, 3.57 mmol) toyield Intermediate 118c (0.899 g, 1.996 mmol, 67%). LC-MS (Method A2)RT=0.85 min, MS (ESI) m/z: 450.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.67(d, J=1.1 Hz, 1H), 7.62-7.59 (m, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.28 (s,2H), 4.77 (s, 2H), 2.59 (dt, J=13.6, 6.7 Hz, 1H), 2.04-1.92 (m, 6H),1.89-1.81 (m, 2H), 1.17 (d, J=6.8 Hz, 6H).

Intermediate 118d4′-((2-isopropyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110d using Intermediate118c (0.400 g, 1.776 mmol) to yield Intermediate 118d (0.398 g, 0.800mmol, 90%). ¹H NMR (400 MHz, CDCl₃) δ 7.90 (s, 1H), 7.84 (dd, J=7.7, 1.1Hz, 1H), 7.74 (d, J=7.7 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.24 (s, 2H),4.77 (s, 2H), 2.65-2.55 (m, 1H), 2.05-1.93 (m, 6H), 1.88-1.80 (m, 2H),1.26-1.24 (m, 12H), 1.17 (d, J=6.8 Hz, 6H).

Intermediate 118e:4′-((2-isopropyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110e using Intermediate118d (0.050 g, 0.101 mmol) and 2-bromo-4-methylpyridine (0.052 g, 0.302mmol) to yield Intermediate 118e (0.040 g, 0.086 mmol, 86%). LC-MS(Method A2) RT=0.75 min, MS (ESI) m/z: 463.1 (M+H)⁺.

Example 118:2-isopropyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 118e(0.040 g, 0.086 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 12-52% B over 22 minutes, then a4-minute hold at 100% B; Flow: 20 mL/min Example 118 (0.0078 g, 0.015mmol, 16%): LC-MS (Method A2) RT=0.68 min, MS (ESI) 506.2 (M+H)⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.54 (d, J=4.9 Hz, 1H), 8.17 (br d, J=8.1 Hz, 1H),8.11 (s, 1H), 7.94 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.31-7.16 (m, 3H),7.08 (d, J=8.1 Hz, 2H), 4.72 (s, 2H), 2.67 (dt, J=13.6, 6.6 Hz, 1H),2.42 (s, 3H), 1.93-1.78 (m, 6H), 1.69 (br d, J=7.6 Hz, 2H), 1.06 (d,J=6.7 Hz, 6H) (1 exchangeable proton not observed).

Example 119:2-cyclopropyl-3-((5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 119a: 1-(cyclopropanecarboxamido)cyclopentane-1-carboxamide

To a solution of 1-aminocyclopentane-1-carboxamide (1.00 g, 7.80 mmol)in DCM (16 mL) was added TEA (2.72 mL, 19.50 mmol). The mixture wascooled with an ice bath. Cyclopropanecarbonyl chloride (1.142 g, 10.92mmol) in DCM (4 mL) was added dropwise to the stirred solution, and thereaction mixture was at RT for 18 hours. The reaction was diluted withH₂O and DCM. The organic phase was collected. The aqueous phase wasextracted (2×) with DCM. The combined organic phase was washed withbrine, dried over sodium sulfate, and concentrated to give Intermediate119a (0.889 g, 4.53 mmol, 58.1% yield) as a solid. RT=0.49 min, MS (ESI)m/z: 197.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 5.91 (br s, 2H), 5.76-5.57(m, 1H), 2.49-2.25 (m, 1H), 2.07 (br d, J=16.7 Hz, 1H), 1.93-1.74 (m,2H), 1.67-1.28 (m, 2H), 1.28-1.19 (m, 2H), 1.03-0.97 (m, 2H), 0.90-0.82(m, 2H), 0.81-0.74 (m, 1H).

Intermediate 119b: 2-cyclopropyl-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 110b using Intermediate119a (0.599 g, 3.06 mmol) to yield Intermediate 119b (0.258 g, 0.1.448mmol, 47%). LC-MS (Method A2) RT=0.43 min, MS (ESI) m/z: 178.0 (M+H)⁺.¹H NMR (400 MHz, CDCl₃) δ 2.00-1.86 (m, 3H), 1.85-1.72 (m, 2H),1.30-1.22 (m, 1H), 1.08-1.01 (m, 3H), 0.97-0.89 (m, 1H).

Intermediate 119c:5-bromo-4′-((2-cyclopropyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110c using Intermediate119b (0.473 g, 2.65 mmol) and Intermediate I-002 (1.12 g, 3.19 mmol) toyield Intermediate 119c (0.510 g, 1.14 mmol, 43%). LC-MS (Method A2)RT=0.84 min, MS (ESI) m/z: 449.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.67(dd, J=1.8, 0.7 Hz, 1H), 7.62-7.60 (m, 2H), 7.52 (d, J=8.4 Hz, 2H), 7.34(d, J=8.4 Hz, 2H), 4.87 (s, 2H), 2.01-1.89 (m, 6H), 1.80-1.72 (m, 2H),1.49 (tt, J=8.2, 5.0 Hz, 1H), 1.00-0.94 (m, 2H), 0.89-0.82 (m, 2H).

Intermediate 119d:4′-((2-cyclopropyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110d using Intermediate119c (0.510 g, 1.137 mmol) to yield Intermediate 119d (0.448 g, 0.904mmol, 79%). ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.85 (dd, J=7.7, 1.1Hz, 1H), 7.77-7.71 (m, 1H), 7.58-7.53 (m, 2H), 7.31 (d, J=8.4 Hz, 2H),4.86 (s, 2H), 2.02-1.91 (m, 6H), 1.80-1.74 (m, 2H), 1.53-1.47 (m, 1H),1.26 (d, J=3.3 Hz, 12H), 1.00-0.94 (m, 2H), 0.89-0.82 (m, 2H).

Intermediate 119e:4′-((2-cyclopropyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4-methoxypyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110e using Intermediate119d (0.051 g, 0.272 mmol) and 2-bromo-4-methoxy-pyridine (0.052 g,0.272 mmol) to yield Intermediate 119e (0.040 g, 0.084 mmol, 92%). LC-MS(Method A2) RT=0.66 min, MS (ESI) m/z: 477.1 (M+H)⁺.

Example 119:2-cyclopropyl-3-((5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 119e(0.040 g, 0.084 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 ACN: H₂O with 0.1% trifluoroacetic acid; Gradient: 0-40% Bover 22 minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min Example119 (0.0025 g, 0.0048 mmol, 5%): LC-MS (Method A2) RT=0.58 min, MS (ESI)m/z: 520.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (d, J=5.5 Hz, 1H),8.20 (br d, J=7.9 Hz, 1H), 8.16 (s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.64(d, J=1.8 Hz, 1H), 7.22-7.17 (m, 2H), 7.16-7.11 (m, 2H), 6.99 (dd,J=5.5, 2.1 Hz, 1H), 4.81 (s, 2H), 3.94 (s, 3H), 1.86-1.78 (m, 6H), 1.72(br t, J=5.3 Hz, 1H), 1.62 (br d, J=7.0 Hz, 2H), 0.86-0.76 (m, 4H) (1exchangeable proton not observed).

Example 120:2-cyclopropyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 120a:4′-((2-cyclopropyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Example 110e using Intermediate119d (0.045 g, 0.091 mmol) and 2-bromo-4-methylpyridine (0.047 g, 0.272mmol) to yield Intermediate 120a (0.040 g, 0.087 mmol, 96%). LC-MS(Method A2) RT=0.74 min, MS (ESI) m/z: 461.1 (M+H)⁺.

Example 120:2-cyclopropyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Synthesized in an analogous manner to Example 99 using Intermediate 120a(0.040 g, 0.087 mmol). Purified using preparative LC-MS with thefollowing conditions: Column: XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 10-50% B over 19 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min Example 120 (0.0022 g, 0.00384mmol, 3.9%): LC-MS (Method A2) RT=0.62 min, MS (ESI) m/z: 504.1 (M+H)⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (br d, J=4.6 Hz, 1H), 8.19 (br s, 1H),8.13 (br s, 1H), 7.97 (br s, 1H), 7.76 (br s, 1H), 7.23 (br d, J=4.6 Hz,1H), 7.17 (br s, 2H), 7.13 (br s, 2H), 4.80 (s, 2H), 2.41 (s, 3H),1.86-1.78 (m, 6H), 1.75-1.66 (m, 2H), 1.61 (br s, 2H), 0.84-0.79 (m,3H). (1 exchangeable proton not observed).

Example 121:3-(4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(3,3-difluoropiperidin-1-yl)-[1,1′-biphenyl]-2-yl)-1,2,4-oxadiazol-5(4H)-one

Intermediate 121a:4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(3,3-difluoropiperidin-1-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Intermediate 99b usingIntermediate 99a (0.135 g, 0.321 mmol) and 3,3-difluoropiperidinehydrochloride (0.025 g, 0.032 mmol) to yield Intermediate 121a (0.100 g,0.198 mmol, 62%). LC-MS (Method A2) RT=0.94 min, MS (ESI) m/z: 505.1(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.59 (d, J=8.6 Hz, 1H), 7.52 (d, J=8.1Hz, 2H), 7.26 (d, J=7.9 Hz, 2H), 6.91-6.83 (m, 2H), 4.74 (s, 2H), 3.59(t, J=11.4 Hz, 2H), 3.45-3.38 (m, 2H), 2.39-2.31 (m, 2H), 2.16-1.80 (m,12H), 1.61 (dt, J=15.5, 7.6 Hz, 2H), 1.35 (dq, J=15.0, 7.4 Hz, 2H), 0.88(t, J=7.3 Hz, 3H).

Intermediate 121b:(Z)-4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(3,3-difluoropiperidin-1-yl)-N′-hydroxy-[1,1′-biphenyl]-2-carboximidamide

To a vial containing hydroxylamine hydrochloride (174 mg, 2.497 mmol)and potassium t-butoxide (233 mg, 2.081 mmol) was added ethanol (2081μl). The mixture was stirred vigorously at RT for 1 min before beingpipetted into a vial containing Intermediate 121a (105 mg, 0.208 mmol).The reaction was heated at 85° C. for 48 hours. The reaction mixture wasdiluted with DCM and washed with H₂O. The organic phase was concentratedand azeotroped with toluene to yield Intermediate 121b (0.015 g, 0.028mmol, 13%) which was used without further purification in the next step.LC-MS (Method A2) RT=0.79 min, MS (ESI) m/z: 538.1 (M+H)⁺.

Example 121:3-(4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(3,3-difluoropiperidin-1-yl)-[1,1′-biphenyl]-2-yl)-1,2,4-oxadiazol-5(4H)-one

To a vial charged with Intermediate 121b (15 mg, 0.028 mmol) was addedDMF (2 mL) followed by DBU (0.021 mL, 0.139 mmol) and CDI (22.62 mg,0.139 mmol). The reaction was allowed to stir at RT for 18 hours. Thereaction was filtered and concentrated. The crude reaction mixture wasdissolved in 2 mL of DMF. The crude material was purified viapreparative LC-MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂O with 0.1%trifluoroacetic acid; Gradient: 20-65% B over 30 minutes, then a3-minute hold at 100% B; Flow: 20 mL/min to yield Example 121 (0.005 g,0.0085 mmol, 31%): LC-MS (Method A2) RT=0.92 min, MS (ESI) m/z: 564.1(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.44 (d, J=8.5 Hz, 1H), 7.30 (d,J=7.6 Hz, 2H), 7.16 (d, J=7.9 Hz, 2H), 7.10 (d, J=8.5 Hz, 1H), 6.92 (br.s., 1H), 4.72 (s, 2H), 3.69 (t, J=11.6 Hz, 2H), 3.51 (d, J=7.9 Hz, 1H),3.42 (br. s., 1H), 2.33 (t, J=7.3 Hz, 2H), 2.07 (br. s., 2H), 1.90-1.81(m, 6H), 1.77 (br. s., 2H), 1.68 (br. s., 2H), 1.56-1.41 (m, 2H),1.34-1.24 (m, 2H), 0.80 (t, J=7.3 Hz, 3H) (one exchangeable proton notobserved).

Example 122:2-butyl-3-((4″-methyl-6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 122a:4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-chloro-[1,1′-biphenyl]-2-carbonitrile

Intermediate 033a (1.21 g, 2.95 mmol), 4-chloro-2-iodobenzonitrile(0.932 g, 3.54 mmol), and PdCl₂(dppf)-CH₂Cl₂Adduct (0.241 g, 0.295 mmol)were dissolved in toluene (23.6 mL), ethanol (5.90 mL), and tripotassiumphosphate (2 M aq, 2.95 mL, 5.90 mmol) and the reaction was degassed for15 minutes by bubbling with Ar. The reaction was sealed and heated at100° C. for 18 hours. The reaction was cooled to ambient temperature,filtered through celite, diluted with EtOAc, washed with saturatedNaHCO₃, then brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.The crude material was purified by column chromatography (ISCO, 80 gsilica gel column, 29 minute gradient of 0 to 100% EtOAc in hexanes) togive Intermediate 122a (1.03 g, 2.45 mmol, 83%). LC-MS (Method A2)RT=1.00 min, MS (ESI) m/z: 420.3 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.72(d, J=8.3 Hz, 1H), 7.58-7.54 (m, 2H), 7.52 (d, J=2.2 Hz, 1H), 7.46 (dd,J=8.4, 2.1 Hz, 1H), 7.32 (d, J=8.3 Hz, 2H), 4.77 (s, 2H), 2.40-2.33 (m,2H), 2.06-1.94 (m, 6H), 1.90-1.83 (m, 2H), 1.67-1.60 (m, 2H), 1.42-1.33(m, 2H), 0.90 (t, J=7.4 Hz, 3H).

Intermediate 122b:2-butyl-3-((5′-chloro-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 122a (1.03 g, 2.45 mmol) was dissolved in toluene (24.5mL). Dibutyltin oxide (0.611 g, 2.45 mmol) and TMS-N₃ (1.63 mL, 12.3mmol) were added. The reaction was sealed in a pressure vial and heatedat 100° C. for 18 hours. The reaction was cooled to ambient temperatureand diluted with EtOAc into a large erlenmeyer. A 10% aqueous solutionof ceric ammonium nitrate (6.72 g, 12.3 mmol) was added slowly to mildbubbling. An aliquot of the reaction was added to an aqueous 0.02 M irontrichloride solution to confirm complete consumption of azide (no redcolor). The layers were separated and the organic layer was furtherwashed twice with saturated NH₄Cl, then brine, dried (Na₂SO₄), filtered,and concentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 40 g silica gel olumn, 19 minute gradient of 0 to20% MeOH in DCM) to give Intermediate 122b (0.946 g, 2.04 mmol, 83%) asa tan solid. LC-MS (Method A2) RT=0.93 min, MS (ESI) m/z: 463.3 (M+H)⁺.¹H NMR (500 MHz, CDCl₃) δ 8.03 (d, J=8.5 Hz, 1H), 7.56 (dd, J=8.3, 2.2Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.25-7.17 (m, 4H), 4.73 (s, 2H),2.33-2.27 (m, 2H), 2.06 (d, J=6.6 Hz, 1H), 1.99-1.93 (m, 2H), 1.93-1.86(m, 4H), 1.80 (dd, J=11.6, 5.0 Hz, 3H), 1.58 (dt, J=15.3, 7.6 Hz, 2H),1.39-1.30 (m, 2H), 0.88 (t, J=7.3 Hz, 3H)

Intermediate 122c:2-butyl-3-((5′-chloro-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 122b (0.900 g, 1.94 mmol), TEA (0.352 mL, 2.53 mmol) andtritylchloride (0.623 g, 2.24 mmol) were dissolved in DCM (9.72 mL).After stirring for 3 hours, the reaction was diluted with DCM and washedwith 1M K₂HPO₄, then brine, then dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 80 g silica gel column, 29 minute gradient of 0 to100% EtOAc in hexanes) to give Intermediate 122c (0.879 g, 1.25 mmol,63%) as a white solid. LC-MS (Method A2) RT=1.26 min, MS (ESI) m/z:705.5 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.92 (d, J=8.5 Hz, 1H), 7.46(dd, J=8.3, 2.2 Hz, 1H), 7.41-7.35 (m, 4H), 7.32-7.27 (m, 6H), 7.11 (d,J=8.0 Hz, 2H), 6.97-6.90 (m, 8H), 2.25 (t, J=7.8 Hz, 2H), 2.06-1.95 (m,6H), 1.84 (br. s., 2H), 1.61-1.52 (m, 2H), 1.34-1.26 (m, 2H), 0.87 (t,J=7.3 Hz, 3H).

Example 122:2-butyl-3-((4″-methyl-6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 122c (20 mg, 0.028 mmol), p-tolylboronic acid (11.6 mg,0.085 mmol), and 2nd Generation XPHOS Precatalyst (2.23 mg, 2.84 mol)were dissolved in toluene (1.13 mL), EtOH (284 μL), and tripotassiumphosphate (2 M aq, 28.4 μL, 0.057 mmol). The reaction was heated at 100°C. for 18 hours. The reaction was cooled to ambient temperature thendiluted with EtOAc, filtered through celite/Na₂SO₄ and concentrated invacuo. The residue was dissolved in DCM (1.42 mL). Triethylsilane (22.6μL, 0.142 mmol) and TFA (109 μL, 1.42 mmol) were added. After 30minutes, the reaction was concentrated in vacuo. The crude material waspurified via preparative LC-MS with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂Owith 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂O with 0.1%trifluoroacetic acid; Gradient: 40-80% B over 19 minutes, then a5-minute hold at 100% B; Flow: 20 mL/min to give Example 122 (3.9 mg,7.14 μmol, 25%). LC-MS (Method A2) RT=1.14 min, MS (ESI) m/z: 519.5(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (d, J=7.3 Hz, 1H), 7.74-7.64(m, 4H), 7.31 (d, J=7.9 Hz, 2H), 7.16 (d, J=7.3 Hz, 2H), 7.07 (d, J=7.6Hz, 2H), 4.67 (s, 2H), 2.35 (s, 3H), 2.29 (t, J=7.5 Hz, 2H), 1.89-1.77(m, 6H), 1.67 (d, J=6.4 Hz, 2H), 1.45 (quin, J=7.4 Hz, 2H), 1.24 (dq,J=14.6, 7.1 Hz, 2H), 0.78 (t, J=7.3 Hz, 3H) (1 exchangeable proton notobserved).

Example 123:2-butyl-3-((5′-(isothiazol-3-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 123a:5-bromo-4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 033a was reacted with 4-bromo-2-iodobenzonitrile in amethod analogous to Intermediate 122a to give Intermediate 123a. LC-MS(Method A2) RT=0.89 min, MS (ESI) m/z: 464 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 7.69 (d, J=1.4 Hz, 1H), 7.66-7.59 (m, 2H), 7.55 (d, J=8.3 Hz,2H), 7.32 (d, J=8.3 Hz, 2H), 4.77 (s, 2H), 2.40-2.33 (m, 2H), 2.06-1.94(m, 5H), 1.91-1.82 (m, 2H), 1.63 (dt, J=15.4, 7.7 Hz, 3H), 1.42-1.32 (m,2H), 0.90 (t, J=7.4 Hz, 3H).

Intermediate 123b:3-((5′-bromo-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 123a was reacted in a method analogous to Intermediate 122bto give Intermediate 123b. LC-MS (Method A2) RT=0.79 min, MS (ESI) m/z:507 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.93 (d, J=8.3 Hz, 1H), 7.71 (dd,J=8.3, 1.9 Hz, 1H), 7.63 (d, J=1.9 Hz, 1H), 7.25-7.20 (m, 2H), 7.18-7.13(m, 2H), 4.72 (s, 2H), 2.34-2.26 (m, 2H), 1.99-1.87 (m, 6H), 1.85-1.74(m, 3H), 1.58 (dt, J=15.3, 7.6 Hz, 2H), 1.37-1.32 (m, 2H), 0.88 (t,J=7.4 Hz, 3H).

Intermediate 123c:3-((5′-bromo-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 123b was reacted in a method analogous to Intermediate 122cto give Intermediate 123c. LC-MS (Method A2) RT=1.09 min, MS (ESI) m/z:750 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.85 (d, J=8.3 Hz, 1H), 7.62 (dd,J=8.3, 1.9 Hz, 1H), 7.55 (d, J=2.2 Hz, 1H), 7.40-7.35 (m, 3H), 7.32-7.26(m, 7H), 7.11 (d, J=8.0 Hz, 2H), 6.96-6.91 (m, 7H), 4.59 (s, 2H),2.28-2.23 (m, 2H), 2.05-1.97 (m, 6H), 1.84 (d, J=5.8 Hz, 2H), 1.33-1.27(m, 4H), 0.87 (t, J=7.3 Hz, 3H).

Intermediate 123d:2-butyl-3-((5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 123c (540 mg, 0.720 mmol), bispinacolatodiboron (274 mg,1.08 mmol), and KOAc (177 mg, 1.80 mmol) were dissolved in 1,4-dioxane(7.20 mL) and degassed for 5 minutes by bubbling with Ar.PdCl₂(dppe-CH₂Cl₂Adduct (47.1 mg, 0.058 mmol) was added and the reactiondegassed for an additional 10 minutes. The reaction was heated at 130°C. in the microwave for 60 minutes. The reaction was diluted with EtOAcand washed with H₂O then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The crude material was purified by columnchromatography (ISCO, 40 g silica gel column, 19 minute gradient of 0 to100% EtOAc in hexanes) to give Intermediate 123d (350 mg, 0.439 mmol,61%) as a white solid. LC-MS (Method A2) RT=1.12 min, MS (ESI) 798(M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.99 (d, J=7.7 Hz, 1H), 7.90 (d, J=6.9Hz, 1H), 7.80 (s, 1H), 7.41-7.34 (m, 5H), 7.31-7.26 (m, 2H), 7.13 (d,J=8.0 Hz, 2H), 6.97-6.90 (m, 10H), 4.59 (s, 2H), 2.28-2.21 (m, 2H),2.09-1.97 (m, 6H), 1.88-1.81 (m, 2H), 1.37 (s, 12H), 1.35-1.30 (m, 4H),0.89 (t, J=7.3 Hz, 3H).

Example 123:2-butyl-3-((5′-(isothiazol-3-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 123d was reacted with 3-bromoisothiazole in a methodanalogous to Example 122 to give Example 123 (5.9 mg, 11.5 μmol, 46%).LC-MS (Method A1) RT=1.39 min, MS (ESI) m/z: 512.4 (M+H)⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.18 (d, J=4.6 Hz, 1H), 8.12 (br d, J=7.9 Hz, 1H),8.09-8.01 (m, 2H), 7.75 (br d, J=7.9 Hz, 1H), 7.17 (br d, J=7.9 Hz, 2H),7.07 (br d, J=7.9 Hz, 2H), 4.68 (s, 2H), 2.32 (t, J=7.6 Hz, 2H),1.90-1.77 (m, 6H), 1.67 (br d, J=6.7 Hz, 2H), 1.49 (quin, J=7.5 Hz, 2H),1.27 (dq, J=14.9, 7.4 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H) (1 exchangeableproton not observed). The compounds listed in the table below weresynthesized using the same methods that were used to prepare Example 122and Example 123.

LC-MS m/z Ex [M + H]⁺; RT # Structure MW (Method) ¹H NMR 124

561.677 562.0; 1.44 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (brs, 1H), 7.98-7.87 (m, 5H), 7.82-7.73 (m, 2H), 7.18 (br d, J = 7.7 Hz,2H), 7.08 (br d, J = 8.0 Hz, 2H), 4.68 (s, 2H), 2.81 (d, J = 4.4 Hz,3H), 2.29 (br t, J = 7.4 Hz, 2H), 1.90-1.76 (m, 6H), 1.66 (br d, J = 7.7Hz, 2H), 1.50-1.41 (m, 2H), 1.29-1.18 (m, 2H), 0.78 (br t, J = 7.2 Hz,3H) (1 exchangeable proton not observed) 125

505.613 505.9; 1.48 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 9.03 (d,J = 1.6 Hz, 1H), 8.62 (d, J = 3.8 Hz, 1H), 8.24 (br d, J = 8.0 Hz, 1H),7.90 (dd, J = 8.0, 1.6 Hz, 1H), 7.84-7.74 (m, 2H), 7.53 (dd, J = 7.9,4.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.1 Hz, 2H), 4.69(s, 2H), 2.31 (t, J = 7.5 Hz, 2H), 1.90-1.76 (m, 6H), 1.67 (br d, J =6.6 Hz, 2H), 1.49 (quin, J = 7.5 Hz, 2H), 1.27 (dq, J = 14.9, 7.4 Hz,2H), 0.81 (t, J = 7.3 Hz, 3H) (1 exchangeable proton not observed) 126

534.651 535.2; 1.48 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (brd, J = 8.2 Hz, 1H), 7.81-7.71 (m, 3H), 7.45 (br d, J = 7.9 Hz, 2H),7.29-7.04 (m, 5H), 4.73 (s, 2H), 4.56 (s, 2H), 2.38 (br t, J = 7.4 Hz,2H), 1.92-1.66 (m, 7H), 1.54- 1.41 (m, 2H), 1.30-1.18 (m, 4H), 0.80 (brt, J = 7.2 Hz, 3H) (1 exchangeable proton not observed) 127

522.616 523.0; 1.86 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ7.79-7.72 (m, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.64-7.57 (m, 3H),7.55-7.49 (m, 1H), 7.24-7.14 (m, 3H), 7.02 (br d, J = 8.0 Hz, 2H), 4.65(s, 2H), 2.30 (br t, J = 7.5 Hz, 2H), 1.92-1.75 (m, 8H), 1.66 (br d, J =7.9 Hz, 2H), 1.44 (quin, J = 7.3 Hz, 2H), 1.27-1.17 (m, 3H) (1exchangeable proton not observed) 128

534.651 535.0; 1.40 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 7.60(dd, J = 18.5, 7.8 Hz, 2H), 7.45-7.31 (m, 5H), 7.14 (br d, J = 7.9 Hz,2H), 6.99 (br d, J = 7.9 Hz, 2H), 4.64 (s, 2H), 4.49 (s, 2H), 2.73 (s,1H), 2.30 (br t, J = 7.5 Hz, 2H), 1.88-1.75 (m, 6H), 1.66 (br d, J = 6.7Hz, 2H), 1.46 (quin, J = 7.5 Hz, 2H), 1.24 (sxt, J = 7.4 Hz, 2H), 0.77(t, J = 7.3 Hz, 3H) (1 exchangeable proton not observed) 129

519.640 520.1; 1.37 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.83 (s,1H), 8.47 (s, 1H), 8.08 (s, 1H), 7.91 (br d, J = 7.9 Hz, 1H), 7.82 (s,1H), 7.78 (d, J = 7.9 Hz, 1H), 7.20 (br d, J = 7.9 Hz, 2H), 7.10 (br d,J = 7.9 Hz, 2H), 4.69 (s, 2H), 2.39 (s, 3H), 2.31 (br t, J = 7.5 Hz,2H), 1.89-1.79 (m, 6H), 1.67 (br d, J = 5.8 Hz, 2H), 1.49 (quin, J = 7.5Hz, 2H), 1.33-1.23 (m, 2H), 0.82 (t, J = 7.3 Hz, 3H) (1 exchangebleproton not observed) 130

510.653 511.4; 1.61 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.11 (brs, 1H), 7.91 (br d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.75-7.67 (m, 3H),7.21-7.14 (m, 2H), 7.10 (br d, J = 7.9 Hz, 2H), 4.69 (s, 2H), 2.31 (brt, J = 7.5 Hz, 2H), 1.90- 1.78 (m, 6H), 1.68 (br d, J = 5.2 Hz, 2H),1.50 (quin, J = 7.6 Hz, 2H), 1.28 (sxt, J = 7.4 Hz, 2H), 0.82 (t, J =7.3 Hz, 3H) (1 exchangeable proton not observed) 131

510.653 511.2; 1.71 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (s,1H), 7.83 (br s, 1H), 7.72 (br s, 3H), 7.65 (br d, J = 4.9 Hz, 1H),7.24-7.05 (m, 4H), 4.69 (s, 2H), 2.31 (br t, J = 7.2 Hz, 2H), 1.93-1.79(m, 6H), 1.67 (br s, 2H), 1.49 (quin, J = 7.4 Hz, 2H), 1.34-1.22 (m,2H), 0.82 (t, J = 7.2 Hz, 3H) (1 exchangeable proton not observed) 132

535.639 536.5; 1.36 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.60 (s,1H), 8.33 (d, J = 2.1 Hz, 1H), 7.90 (br d, J = 8.1 Hz, 1H), 7.82 (s,1H), 7.79-7.73 (m, 2H), 7.20 (br d, J = 7.9 Hz, 2H), 7.08 (br d, J = 8.0Hz, 2H), 4.68 (s, 2H), 3.92 (s, 3H), 2.31 (br t, J = 7.4 Hz, 2H),1.89-1.77 (m, 6H), 1.67 (br d, J = 6.6 Hz, 2H), 1.54-1.42 (m, 2H),1.30-1.24 (m, 2H), 0.80 (br t, J = 7.3 Hz, 3H) (1 exchangeable protonnot observed) 133

575.703 576.2; 1.43 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 7.85 (brd, J = 7.9 Hz, 2H), 7.82 (br d, J = 7.9 Hz, 1H), 7.74 (br d, J = 7.9 Hz,1H), 7.72 (s, 1H), 7.52 (br d, J = 8.2 Hz, 2H), 7.20 (br d, J = 7.9 Hz,2H), 7.06 (br d, J = 7.9 Hz, 2H), 4.68 (s, 2H), 2.99 (br d, J = 17.4 Hz,6H), 2.32 (br t, J = 7.5 Hz, 2H), 1.90-1.79 (m, 6H), 1.67 (br d, J = 5.8Hz, 2H), 1.49 (quin, J = 7.5 Hz, 2H), 1.31-1.24 (m, 2H), 0.81 (t, J =7.3 Hz, 3H) (1 exchangeable proton not observed) 134

588.623 589.2; 1.99 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (brd, J = 8.9 Hz, 2H), 7.84-7.77 (m, 1H), 7.74 (br d, J = 8.2 Hz, 1H), 7.71(s, 1H), 7.48 (br d, J = 7.9 Hz, 2H), 7.20 (br d, J = 7.9 Hz, 2H), 7.06(br d, J = 7.9 Hz, 2H), 4.68 (s, 2H), 2.32 (br t, J = 7.5 Hz, 2H),1.89-1.78 (m, 6H), 1.67 (br d, J = 4.9 Hz, 2H), 1.49 (quin, J = 7.5 Hz,2H), 1.32-1.22 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H) (1 exchangeable protonnot observed) 135

540.606 541.1; 2.27 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 7.78 (q,J = 7.9 Hz, 2H), 7.67 (s, 1H), 7.56-7.47 (m, 2H), 7.39- 7.31 (m, 1H),7.17 (br d, J = 7.9 Hz, 2H), 7.09 (br d, J = 7.9 Hz, 2H), 4.68 (s, 2H),2.29 (br t, J = 7.5 Hz, 2H), 1.90-1.76 (m, 6H), 1.67 (br d, J = 6.1 Hz,2H), 1.46 (quin, J = 7.3 Hz, 2H), 1.25 (sxt, J = 7.3 Hz, 2H), 0.79 (t, J= 7.3 Hz, 3H) (1 exchangeable proton not observed) 136

571.620 572.4; 1.60 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (brs, 1H), 7.98-7.90 (m, 1H), 7.84 (s, 1H), 7.82-7.76 (m, 1H), 7.70 (s,1H), 7.52-7.44 (m, 1H), 7.15-7.07 (m, 2H), 6.98 (br s, 2H), 4.65 (s,2H), 2.33 (d, J = 5.3 Hz, 2H), 2.23-2.15 (m, 1H), 1.89-1.73 (m, 6H),1.59 (d, J = 5.9 Hz, 2H), 1.41 (br s, 2H), 1.12 (br s, 2H), 0.76-0.65(m, 3H) (1 exchangeable proton not observed) 137

511.641 512.5; 1.33 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s,1H), 8.42 (br s, 1H), 8.15 (br d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.75(d, J = 8.1 Hz, 1H), 7.16 (br d, J = 7.8 Hz, 2H), 7.10 (br d, J = 8.0Hz, 2H), 4.69 (s, 2H), 2.30 (br t, J = 7.4 Hz, 2H), 1.92-1.77 (m, 6H),1.67 (br d, J = 6.8 Hz, 2H), 1.55-1.42 (m, 2H), 1.32-1.20 (m, 2H), 0.80(br t, J = 7.2 Hz, 3H) (1 exchangeable proton not observed) 138

519.640 520.1; 1.55 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.20 (brd, J = 7.6 Hz, 1H), 8.15 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.81 (t, J =7.6 Hz, 1H), 7.77 (br d, J = 6.4 Hz, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.17(br d, J = 7.0 Hz, 2H), 7.09 (br d, J = 7.9 Hz, 2H), 4.69 (s, 2H), 2.55(s, 3H), 2.31 (t, J = 7.5 Hz, 2H), 1.93-1.76 (m, 6H), 1.68 (br d, J =7.6 Hz, 2H), 1.47 (quin, J = 7.5 Hz, 2H), 1.26 (dq, J = 14.8, 7.4 Hz,2H), 0.81 (t, J = 7.3 Hz, 3H) (1 exchangeable proton not observed) 139

519.640 519.9; 1.52 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (d,J = 4.9 Hz, 1H), 8.06 (br d, J = 7.9 Hz, 1H), 8.01 (s, 1H), 7.89 (s,1H), 7.70 (br s, 1H), 7.18 (br dd, J = 10.7, 5.5 Hz, 3H), 7.02 (br d, J= 7.9 Hz, 2H), 4.67 (s, 2H), 2.39 (s, 3H), 2.33 (br t, J = 7.5 Hz, 2H),1.94- 1.77 (m, 6H), 1.68 (br d, J = 7.0 Hz, 2H), 1.50 (quin, J = 7.6 Hz,2H), 1.33-1.22 (m, 2H), 0.81 (t, J = 7.3 Hz, 3H) (1 exchangeable protonnot observed) 140

505.613 506.2; 0.71 min (Method A2) ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (brd, J = 4.3 Hz, 1H), 8.12-8.00 (m, 3H), 7.89 (br t, J = 7.2 Hz, 1H), 7.73(br d, J = 7.6 Hz, 1H), 7.41-7.32 (m, 1H), 7.19 (br d, J = 7.6 Hz, 2H),7.03 (br d, J = 7.9 Hz, 2H), 4.67 (s, 2H), 2.34 (br t, J = 7.5 Hz, 2H),1.90- 1.78 (m, 6H), 1.68 (br d, J = 7.3 Hz, 2H), 1.51 (quin, J = 7.5 Hz,2H), 1.29 (dq, J = 15.0, 7.5 Hz, 2H), 0.83 (t, J = 7.3 Hz, 3H) (1exchangeable proton not observed) 141

535.652 536.1; 0.68 min (Method A2) ¹H NMR (500 MHz, CDCl₃) δ 8.14 (brd, J = 5.8 Hz, 1H), 7.69-7.57 (m, 3H), 7.14 (d, J = 2.2 Hz, 1H), 6.95(dd, J = 5.9, 2.3 Hz, 1H), 6.90-6.80 (m, 4H), 4.64 (s, 2H), 4.02 (s,3H), 2.32-2.23 (m, 2H), 2.10-1.95 (m, 7H), 1.89-1.81 (m, 1H), 1.62 (dt,J = 15.4, 7.7 Hz, 2H), 1.36 (dq, J = 15.0, 7.4 Hz, 2H), 0.91 (t, J = 7.4Hz, 3H) (1 exchangeable proton not observed) 142

573.611 574.5; 1.66 min (Method A1) ¹H NMR (500 MHz, DMSO-d₆) δ 8.40 (d,J = 8.2 Hz, 1H), 8.25-8.17 (m, 2H), 8.13 (s, 1H), 7.90 (d, J = 7.6 Hz,1H), 7.81 (d, J = 8.2 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 7.08 (d, J =7.9 Hz, 2H), 4.68 (s, 2H), 2.30 (t, J = 7.6 Hz, 2H), 1.92-1.78 (m, 6H),1.67 (br d, J = 8.2 Hz, 2H), 1.44 (quin, J = 7.5 Hz, 2H), 1.24 (dq, J =14.8, 7.3 Hz, 2H), 0.78 (t, J = 7.3 Hz, 3H) (1 exchangeable proton notobserved)

Example 143:3-(4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-1,2,4-oxadiazol-5(4H)-one

Intermediate 143a:4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

To a solution of Intermediate 033a (160 mg, 0.390 mmol) and Intermediate032a (131 mg, 0.507 mmol) in dioxane (3 mL) was added K₃PO₄ (2 M, aq)(0.585 mL, 1.170 mmol) followed by PdCl₂(dppf)₂ (28.5 mg, 0.039 mmol).The resulting mixture was sparged with Na for 2 minutes before beingsealed and heated at 120° C. for 45 min in the microwave. The reactionmixture was cooled to RT, diluted with EtOAc, washed with 1 M K₂HPO₄,dried over MgSO₄, filtered over Celite, and concentrated. The residuewas purified by

ISCO (40 g, 0-100% EtOAc/Hex) to afford Intermediate 143a (149 mg, 0.323mmol, 83% yield) as a yellow oil. LC-MS (Method A2) RT=0.95 min, MS(ESI) m/z: 462.0 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=7.9 Hz,1H), 7.71-7.64 (m, 2H), 7.64-7.57 (m, 4H), 7.53-7.40 (m, 3H), 7.30 (d,J=8.1 Hz, 2H), 4.76 (s, 2H), 2.39-2.33 (m, 2H), 2.04-1.90 (m, 6H),1.90-1.80 (m, 2H), 1.61 (dt, J=15.5, 7.6 Hz, 2H), 1.42-1.30 (m, 2H),0.88 (t, J=7.4 Hz, 3H).

Intermediate 143b:(Z)-4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-N′-hydroxy-[1,1′:3′,1″-terphenyl]-4′-carboximidamide

To a suspension of Intermediate 143a (145 mg, 0.314 mmol) andhydroxylamine hydrochloride (109 mg, 1.571 mmol) in DMSO (2 mL) wasadded NaHCO₃ (132 mg, 1.571 mmol). The reaction mixture was sealed andheated at 120° C. overnight. The reaction was cooled to RT and H₂O wasadded. The formed solid was filtered and washed with H₂O. The solidresidue was solvated in DCM and washed with 10% LiCl (aq). The organicphase was dried over MgSO₄ and concentrated. The residue was dissolvedin DMF and purified via preparative HPLC with the following conditions:Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95ACN: H₂O with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂Owith 0.1% trifluoroacetic acid; Gradient: 10-100% B over 20 minutes,then a 2-minute hold at 100% B; Flow: 20 mL/min to yield Intermediate143b (9.7 mg, 0.020 mmol. 31%). LC-MS (Method A2) RT=0.69 min, MS (ESI)m/z: 495.1 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.03-7.83 (m, 2H),7.81-7.72 (m, 3H), 7.68 (d, J=7.9 Hz, 1H), 7.56-7.40 (m, 6H), 7.26 (d,J=7.9 Hz, 2H), 4.77 (s, 2H), 2.39 (t, J=7.6 Hz, 2H), 1.87 (d, J=5.8 Hz,6H), 1.72 (br. s., 2H), 1.52 (quin, J=7.4 Hz, 2H), 1.37-1.21 (m, 2H),0.82 (t, J=7.3 Hz, 3H).

Example 143:3-(4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-1,2,4-oxadiazol-5(4H)-one

To a solution of Intermediate 143b (35 mg, 0.071 mmol) in DMF (2 mL) wasadded DBU (0.053 mL, 0.354 mmol) followed by CDI (57.4 mg, 0.354 mmol).The reaction was allowed to stir at RT for 5 minutes. The reactionmixture was quenched with a few drops of methanol, filtered, andpurified via preparative HPLC with the following conditions: Column:XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂Owith 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc;Gradient: 30-85% B over 30 minutes, then a 3-minute hold at 100% B;Flow: 20 mL/min to yield Example 143 (26.2 mg. 0.047 mmol, 67%). LC-MS(Method A2) RT=0.87 min, MS (ESI) m/z: 521.1 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.87 (d, J=8.1 Hz, 1H), 7.81 (d, J=7.5 Hz, 2H), 7.76 (d,J=5.6 Hz, 2H), 7.54-7.48 (m, 2H), 7.47-7.37 (m, 3H), 7.22 (d, J=7.8 Hz,2H), 4.75 (s, 2H), 2.33 (t, J=7.4 Hz, 2H), 1.92-1.79 (m, 6H), 1.73-1.63(m, 2H), 1.49 (quin, J=7.4 Hz, 2H), 1.27 (sxt, J=7.4 Hz, 2H), 0.81 (t,J=7.3 Hz, 3H) One exchangeable proton not observed.

Example 144:3-(4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2,3-difluoro-[1,1′:3′,1″-terphenyl]-4′-yl)-1,2,4-oxadiazol-5(4H)-one

Intermediate 144a:4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2,3-difluoro-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

Synthesized in an analogous manner to Intermediate 143a usingIntermediate 99a (0.135 g, 0.231 mmol) and (2,3-difluorophenyl)boronicacid (0.102 g, 0.643 mmol) to yield Intermediate 144a (0.115 g, 0.231mmol, 71.9% yield): LC-MS (Method A2) RT=1.03 min, MS (ESI) m/z: 498.0(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J=8.1 Hz, 1H), 7.79-7.39 (m,5H), 7.34-7.26 (m, 2H), 7.25-7.15 (m, 2H), 4.75 (d, J=3.3 Hz, 2H),2.40-2.31 (m, 2H), 2.08-1.90 (m, 6H), 1.89-1.79 (m, 2H), 1.66-1.54 (m,2H), 1.42-1.29 (m, 2H), 0.88 (t, J=7.4 Hz, 3H).

Intermediate 144b:(Z)-4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2,3-difluoro-N′-hydroxy-[1,1′:3′,1″-terphenyl]-4′-carboximidamide

Synthesized in an analogous manner to Intermediate 143b usingIntermediate 144a (0.110 g, 0.221 mmol) and potassium tert-butoxide(0.184 g 2.65 mmol) to yield Intermediate 144b (0.035 g, 0.066 mmol, 30%yield): LC-MS (Method A2) RT=0.82 min, MS (ESI) m/z: 531.1 (M+H)⁺. Usedwithout further purification in the next step.

Example 144:3-(4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2,3-difluoro-[1,1′:3′,1″-terphenyl]-4′-yl)-1,2,4-oxadiazol-5(4H)-one

Synthesized in an analogous manner to Intermediate 143 usingIntermediate 144b (0.030 g, 0.057 mmol). Purified via preparative HPLCwith the following conditions: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 ACN: H₂O with 0.1% trifluoroacetic acid; Gradient:25-65% B over 27 minutes, then a 3-minute hold at 100% B; Flow: 20mL/min to yield Example 144 (0.005 g, 0.009 mmol, 16% yield): LC-MS(Method A2) RT=0.98 min, MS (ESI) m/z: 557.0 (M+H)⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 7.81-7.69 (m, 2H), 7.62 (s, 1H), 7.53-7.43 (m, 2H), 7.41-7.27(m, 3H), 7.19 (d, J=7.9 Hz, 2H), 4.72 (s, 2H), 2.32 (t, J=7.5 Hz, 2H),1.89-1.77 (m, 6H), 1.67 (d, J=7.6 Hz, 2H), 1.52-1.41 (m, 2H), 1.30-1.19(m, 2H), 0.78 (t, J=7.3 Hz, 3H). One exchangeable proton not observed.

Example 145:4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylicacid

Intermediate 145a: methyl4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-chloro-[1,1′-biphenyl]-2-carboxylate

Synthesized in an analogous manner to Intermediate 143a usingIntermediate 033a (0.080 g, 0.195 mmol) and methyl4-chloro-2-iodobenzoate (0.0694 g, 0.234 mmol) to yield Intermediate145a (0.050 g, 0.110 mmol, 57% yield): LC-MS (Method A2) RT=0.93 min, MS(ESI) m/z: 453.1 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.4 Hz,1H), 7.39 (dd, J=8.4, 2.2 Hz, 1H), 7.33 (d, J=2.0 Hz, 1H), 7.29-7.24 (m,2H), 7.21-7.16 (m, 2H), 4.73 (s, 2H), 3.63 (s, 3H), 2.37-2.29 (m, 2H),2.06-1.91 (m, 6H), 1.88-1.77 (m, 2H), 1.65-1.54 (m, 2H), 1.34 (dq,J=14.9, 7.4 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H).

Intermediate 145b: methyl4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylate

Synthesized in an analogous manner to Intermediate 143a usingIntermediate 145a (0.050 g, 0.110 mmol) and phenyl boronic acid (0.020g, 0.166 mmol) to yield Intermediate 145b (0.050 g, 0.076 mmol, 69%yield): LC-MS (Method A2) RT=0.99 min, MS (ESI) m/z: 495.1 (M+H)⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.97 (d, J=8.3 Hz, 1H), 7.69-7.62 (m, 3H), 7.58(d, J=1.7 Hz, 1H), 7.52-7.45 (m, 2H), 7.44-7.39 (m, 1H), 7.38-7.35 (m,1H), 7.31-7.27 (m, 1H), 7.23 (d, J=8.0 Hz, 2H), 4.77 (s, 2H), 3.68 (s,3H), 2.41-2.35 (m, 2H), 2.09-1.94 (m, 6H), 1.90-1.80 (m, 2H), 1.67-1.58(m, 2H), 1.43-1.32 (m, 2H), 0.93-0.88 (m, 3H).

Example 145:4″-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylicacid

To a vial containing Intermediate 145b (0.040 g, 0.081 mmol) was addeddioxane (647 μl) followed by MeOH (162 μl). NaOH (1 M aq) (323 μl, 0.323mmol) was added, and the vial was sealed and heated at 80° C. overnight.The reaction mixture was cooled to RT and concentrated. The residue wasdissolved in 2 mL of DMF and purified via preparative LC-MS with thefollowing conditions: Column XBridge C18, 19×200 mm, 5-μm particles;Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5ACN: H₂O with 10 mM NH₄OAc; Gradient: 20-60% B over 20 minutes, then a4-minute hold at 100% B; Flow: 20 mL/min to yield Example 145 (0.015 g,0.030 mmol, 38%): LC-MS (Method A2) RT=0.91 min, MS (ESI) m/z: 481.1(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.81-7.76 (m, 1H), 7.76-7.69 (m,3H), 7.56 (s, 1H), 7.51-7.45 (m, 2H), 7.41 (d, J=7.6 Hz, 3H), 7.18 (d,J=7.9 Hz, 2H), 4.73 (s, 2H), 2.34 (t, J=7.5 Hz, 2H), 1.91-1.77 (m, 6H),1.68 (d, J=7.9 Hz, 2H), 1.48 (quin, J=7.4 Hz, 2H), 1.32-1.23 (m, 2H),0.79 (t, J=7.3 Hz, 3H). One exchangeable proton not observed.

Example 146:3-((6′-(1H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 146a: methyl 3-pentanamidotetrahydrofuran-3-carboxylate

To a solution of methyl 3-aminotetrahydrofuran-3-carb oxylatehydrochloride (1.0 g, 5.5 mmol) in CH₂Cl₂ (18 mL) was added 25% K₂CO₃(18 mL, 36 mmol). The mixture was cooled with an ice bath. Pentanoylchloride (0.91 mL, 7.7 mmol) in CH₂Cl₂ (4 mL) was added dropwise to thestirred solution. The reaction mixture was stirred at 0° C. for 2 h, andat rt for 3 h. The organic phase was collected. The aqueous phase wasextracted (2×) with CH₂Cl₂. The combined organic phase was washed withbrine, dried over Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography (0% to 100% EtOAc in hexane over 15 minusing a 40 g silica gel cartridge) to give Intermediate 146a (1.1 g, 4.8mmol, 87% yield) as an oil. ¹H NMR (500 MHz, CDCl₃) δ 6.05 (br s, 1H),4.17 (d, J=9.6 Hz, 1H), 4.06-3.98 (m, 2H), 3.95 (d, J=9.4 Hz, 1H), 3.78(s, 3H), 2.59 (dt, J=13.2, 7.8 Hz, 1H), 2.28-2.19 (m, 3H), 1.68-1.60 (m,3H), 1.42-1.32 (m, 2H), 0.94 (t, J=7.3 Hz, 3H). LC-MS (Method A2):RT=0.62 min, MS (ESI) m/z: 230.1 (M+H)⁺.

Intermediate 146b: 3-pentanamidotetrahydrofuran-3-carboxamide

A mixture of Intermediate 146a (1.0 g, 4.4 mmol), NaCN (0.032 g, 0.65mmol) in 7.0 N ammonia in MeOH (16 ml, 110 mmol) was sealed in apressure flask and heated at 60° C. over the weekend. LC-MS indicatedcompletion of reaction. Without removing the solvent, the crude productIntermediate 146b was taken to the next step. LC-MS (Method A2): RT=0.50min, MS (ESI) m/z: 215.1 (M+H)⁺.

Intermediate 146c: 2-butyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-one

To a solution of Intermediate 146b (0.9 g, 4.20 mmol) in MeOH (15 mL)was added 2.0 N NaOH (11 mL, 21 mmol). The reaction mixture was heatedat 50° C. overnight. LC-MS indicated completion of reaction. Aftercooling to rt, the reaction mixture was acidified with 3.0 N HCl to pH6-7, extracted with THF/EtOAc (2:1, 3×80 mL). The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated to giveIntermediate 146c (0.57 g, 2.9 mmol, 69% yield) as oil. It was used forthe next step without purification. ¹H NMR (500 MHz, CDCl₃) δ 4.20-4.09(m, 2H), 3.98-3.88 (m, 2H), 2.51 (t, J=7.7 Hz, 2H), 2.35 (dtd, J=12.4,7.9, 1.4 Hz, 1H), 2.16 (dt, J=12.2, 6.0 Hz, 1H), 1.69 (quin, J=7.6 Hz,2H), 1.48-1.39 (m, 2H), 0.98 (td, J=7.3, 0.8 Hz, 3H). LC-MS (Method A2):RT=0.45 min, MS (ESI) m/z: 197.1 (M+H)⁺.

Intermediate 146d-racemate:5-bromo-4′-((2-butyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 146c (570 mg, 2.9 mmol) was dissolved in DMF (12 ml). NaH(128 mg, 3.2 mmol) was added. The mixture was stirred at rt for 15 min,I-002 (1.1 g, 3.1 mmol) was added at 0° C. The reaction mixture wasstirred at rt for 1 h. LC-MS indicated completion of reaction. Thereaction mixture was diluted with EtOAc, washed with saturated NH₄Cl,brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by flash chromatography (5% to 100% EtOAc in hexaneover 18 min using a 40 g silica gel cartridge) to yield Intermediate146d-racemate (920 mg, 2.0 mmol, 68% yield) as a white solid. ¹H NMR(500 MHz, CDCl₃) δ 7.68 (d, J=1.1 Hz, 1H), 7.66-7.60 (m, 2H), 7.56 (d,J=8.3 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 4.84-4.71 (m, 2H), 4.25-4.14 (m,2H), 4.03-3.97 (m, 1H), 3.95-3.90 (m, 1H), 2.44-2.35 (m, 3H), 2.17 (ddd,J=12.2, 6.7, 5.2 Hz, 1H), 1.66 (quin, J=7.6 Hz, 2H), 1.37 (sxt, J=7.4Hz, 2H), 0.90 (t, J=7.3 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃) δ 183.7,163.3, 146.2, 137.4, 136.6, 134.9, 133.2, 131.2, 129.4, 128.0, 127.4,117.9, 110.1, 76.2, 75.8, 69.1, 43.5, 38.0, 28.8, 27.4, 22.3, 13.7.LC-MS (Method A2): RT=0.91 min, MS (ESI) m/z: 466.4 and 468.4 (M+H)⁺.

Intermediate 146e-enantiomer 1:5-bromo-4′-((2-butyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 146d-racemate (920 mg, 2.0 mmol) was resolved into twopeaks by chiral HPLC using a Berger MG II instrument with the followingpreparative chromatographic conditions: Column: Chiralpak AD-H, 30×250mm, 5 micron; Mobile Phase: 15% IPA/85% CO₂; Flow Conditions: 70 mL/min,120 Bar, 40° C.; Detector Wavelength: 220 nm; injection details: 0.5 mLof ˜26 mg/mL in IPA:MeOH (1:1). Purity of each fraction was determinedusing the analytical chromatographic condition below: Instrument: AuroraAnalytical SFC; Column: Chiralpak IC, 4.6×100 mm, 3 micron; MobilePhase: 15% IPA/85% CO₂; Flow Conditions: 1.0 mL/min, 150 Bar, 40° C.;Detector Wavelength: 220 nm; Injection Details: 5 μL of ˜1 mg/mL in IPA.Peak 1 was collected and concentrated to give Intermediate146e-enantiomer 1 (400 mg, 0.86 mmol, 44% yield): enantiomericexcess >99%. Chiral analytical RT=9.4 min ¹H NMR (400 MHz, CDCl₃) δ7.68-7.66 (m, 1H), 7.65-7.59 (m, 2H), 7.57-7.51 (m, 2H), 7.30 (d, J=8.4Hz, 2H), 4.81-4.71 (m, 2H), 4.23-4.13 (m, 2H), 3.98 (d, J=8.6 Hz, 1H),3.93-3.88 (m, 1H), 2.42-2.33 (m, 3H), 2.15 (ddd, J=12.3, 7.0, 5.2 Hz,1H), 1.69-1.60 (m, 2H), 1.43-1.32 (m, 2H), 0.89 (t, J=7.4 Hz, 3H). LC-MS(Method A2): RT=0.92 min, MS (ESI) m/z: 466.1 and 468.1 (M+H)⁺.

Intermediate 146f-enantiomer 2:5-bromo-4′-((2-butyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

Peak 2 was collected from the chiral separation of Intermediate146d-racemate, and concentrated to give Intermediate 146f-enantiomer 2(206 mg, 0.44 mmol, 22% yield): enantiomeric excess 91%. Chiralanalytical RT=11.8 min. ¹H NMR (500 MHz, CDCl₃) δ 7.70 (d, J=1.1 Hz,1H), 7.67-7.61 (m, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H),4.84-4.74 (m, 2H), 4.26-4.15 (m, 2H), 4.03-3.98 (m, 1H), 3.96-3.91 (m,1H), 2.44-2.36 (m, 3H), 2.18 (ddd, J=12.3, 6.9, 5.2 Hz, 1H), 1.67 (dt,J=15.4, 7.7 Hz, 2H), 1.43-1.34 (m, 2H), 0.91 (t, J=7.3 Hz, 3H). LC-MS(Method A2): RT=0.93 min, MS (ESI) m/z: 466.1 and 468.1 (M+H)⁺.

Intermediate 146 g:4″-((2-butyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)[1,1′:3′,1″-terphenyl]-4′-carbonitrile

A solution of Intermediate 146e-enantiomer 1 (30 mg, 0.064 mmol),phenylboronic acid (17 mg, 0.14 mmol) and Pd-XPhos G3 (2.2 mg, 2.6 μmol)in THF (1.5 mL) and K₃PO₄ (1.0 M, 0.13 mL, 0.13 mmol) was degassed withAr for 1 min. The reaction mixture was sealed in a pressure vial andheated at 120° C. in a microwave reactor for 45 min. LC-MS indicatedcompletion of reaction. The reaction mixture was concentrated andpurified by flash chromatography (10% to 100% EtOAc in hexane over 10min using a 4 g silica gel cartridge) to yield Intermediate 146 g (30mg, 0.065 mmol, 100% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ7.85 (d, J=8.0 Hz, 1H), 7.74-7.67 (m, 2H), 7.64 (br dd, J=7.4, 4.4 Hz,4H), 7.54-7.48 (m, 2H), 7.48-7.43 (m, 1H), 7.33 (d, J=8.0 Hz, 2H),4.85-4.73 (m, 2H), 4.26-4.16 (m, 2H), 4.04-3.98 (m, 1H), 3.96-3.91 (m,1H), 2.45-2.37 (m, 3H), 2.22-2.14 (m, 1H), 1.67 (quin, J=7.6 Hz, 2H),1.39 (dq, J=15.0, 7.4 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H). LC-MS (MethodA2): RT=0.96 min, MS (ESI) m/z: 464.2 (M+H)⁺.

Example 146

Intermediate 146 g (30 mg, 0.065 mmol) was dissolved in toluene (1294μl). Bu₂SnO (35 mg, 0.14 mmol) and TMS-N₃ (103 μl, 0.78 mmol) were addedand the reaction sealed in a pressure vial and heated at 100° C.overnight. LC-MS indicated completion of reaction. Toluene was removedby blowing a slow stream of Na. The mixture was purified using apreparative HPLC (method E) to yield Example 146 (22 mg, 0.042 mmol, 65%yield)¹H NMR (500 MHz, CDCl₃) δ 8.10 (d, J=8.0 Hz, 1H), 7.75 (dd, J=8.1,1.8 Hz, 1H), 7.68-7.63 (m, 3H), 7.53-7.47 (m, 2H), 7.47-7.42 (m, 1H),7.28-7.24 (m, 2H), 7.23-7.19 (m, 2H), 4.86 (s, 2H), 4.25-4.15 (m, 2H),4.08-4.01 (m, 2H), 2.68-2.62 (m, 2H), 2.52-2.44 (m, 1H), 2.41-2.34 (m,1H), 1.72 (quin, J=7.7 Hz, 2H), 1.43 (sxt, J=7.4 Hz, 2H), 0.94 (t, J=7.4Hz, 3H). LC-MS (Method A2): RT=0.84 min, MS (ESI) m/z: 507.0 (M+H)⁺.Analytical HPLC purity (Method A2): 98%

Example 147:3-((6′-(1H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 147a:4″-((2-butyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

In a procedure similar to that of 146 g, using Intermediate146f-enantiomer 2 (30 mg, 0.064 mmol), phenylboronic acid (17 mg, 0.14mmol), Pd-XPhos G3 (2.2 mg, 2.6 μmol) and K₃PO₄ salt (1.0 M, 0.13 mL,0.123 mmol), Intermediate 147a (30 mg, 0.065 mmol, 100% yield) wasobtained as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.85 (d, J=8.0 Hz,1H), 7.74-7.67 (m, 2H), 7.64 (br dd, J=7.4, 4.4 Hz, 4H), 7.54-7.48 (m,2H), 7.48-7.43 (m, 1H), 7.33 (d, J=8.0 Hz, 2H), 4.85-4.73 (m, 2H),4.26-4.16 (m, 2H), 4.04-3.98 (m, 1H), 3.96-3.91 (m, 1H), 2.45-2.37 (m,3H), 2.22-2.14 (m, 1H), 1.67 (quin, J=7.6 Hz, 2H), 1.39 (dq, J=15.0, 7.4Hz, 2H), 0.91 (t, J=7.4 Hz, 3H). LC-MS (Method A2): RT=0.96 min, MS(ESI) m/z: 464.2 (M+H)⁺.

Example 147

In a procedure similar to that of Example 146, using Intermediate 147a(30 mg, 0.065 mmol), Bu₂SnO (35 mg, 0.14 mmol) and TMS-N₃ (103 μl, 0.78mmol), Example 147 (19 mg, 0.037 mmol, 56.8% yield) was obtained as awhite solid. ¹H NMR (500 MHz, CDCl₃) δ 8.10 (d, J=8.0 Hz, 1H), 7.75 (dd,J=8.1, 1.8 Hz, 1H), 7.68-7.63 (m, 3H), 7.53-7.47 (m, 2H), 7.47-7.42 (m,1H), 7.28-7.24 (m, 2H), 7.23-7.19 (m, 2H), 4.86 (s, 2H), 4.25-4.15 (m,2H), 4.08-4.01 (m, 2H), 2.68-2.62 (m, 2H), 2.52-2.44 (m, 1H), 2.41-2.34(m, 1H), 1.72 (quin, J=7.7 Hz, 2H), 1.43 (sxt, J=7.4 Hz, 2H), 0.94 (t,J=7.4 Hz, 3H). LC-MS (Method A2): RT=0.84 min, MS (ESI) m/z: 507.0(M+H)⁺. Analytical HPLC purity (Method A2): 100%.

The following examples have been similarly prepared from Intermediate146e-enantiomer 1 and Intermediate 146f-enantiomer 2 with selectedboronic acids as described above for Example 146. Two analytical LC-MSinjections were used to determine the final purity. The retention timeof one of them is reported for each compound and is referred as MethodA1 or Method A2.

LC-MS m/z [M + H]⁺; ¹H NMR RT; Purity (500 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 148

524.6 525.1; 1.70 min; 97% (Method A2) 7.80-7.72 (m, 2H), 7.72-7.61 (m,2H), 7.53-7.44 (m, 1H), 7.40- 7.31 (m, 2H), 7.16 (s, 2H), 7.14- 7.06 (m,2H), 4.70 (s, 2H), 3.98 (br t, J = 7.0 Hz, 2H), 3.78-3.68 (m, 1H), 2.33(br t, J = 7.3 Hz, 2H), 2.17 (dt, J = 12.4, 7.7 Hz, 1H), 2.00 (dt, J =12.0, 5.8 Hz, 1H), 1.48 (quin, J = 7.4 Hz, 2H), 1.32-1.18 (m, 2H), 0.79(t, J = 7.3 Hz, 3H). 149

524.6 525.1; 1.67 min; 95% (Method A2) 7.80-7.72 (m, 2H), 7.72-7.61 (m,2H), 7.54-7.44 (m, 1H), 7.41- 7.30 (m, 2H), 7.20-7.14 (m, 2H), 7.14-7.06(m, 2H), 4.70 (s, 2H), 3.98 (br t, J = 6.9 Hz, 2H), 3.77-3.68 (m, 1H),2.33 (br t, J = 7.5 Hz, 2H), 2.17 (dt, J = 12.5, 7.9 Hz, 1H), 2.00 (dt,J = 12.1, 5.9 Hz, 1H), 1.48 (quin, J = 7.5 Hz, 2H), 1.30-1.20 (m, 2H),0.79 (t, J = 7.3 Hz, 3H). 150

522.6 523.4; 1.49 min; 96% (Method A2) 7.65-7.57 (m, 2H), 7.53 (s, 1H),7.37 (br d, J = 7.6 Hz, 1H), 7.22- 7.12 (m, 3H), 7.05 (br d, J = 7.9 Hz,2H), 6.97 (d, J = 8.2 Hz, 1H), 6.91 (br t, J = 7.3 Hz, 1H), 4.69 (s,2H), 3.99 (br t, J = 6.9 Hz, 2H), 3.79-3.74 (m, 1H), 3.74-3.69 (m, 1H),2.37 (br t, J = 7.3 Hz, 2H), 2.22-2.14 (m, 1H), 2.01 (dt, J = 12.0, 5.8Hz, 1H), 1.52 (quin, J = 7.5 Hz, 2H), 1.29 (dq, J = 14.7, 7.3 Hz, 2H),0.82 (t, J = 7.3 Hz, 3H). 151

522.6 523.2; 1.45 min; 97% (Method A2) 7.62 (s, 2H), 7.53 (s, 1H), 7.37(br d, J = 7.3 Hz, 1H), 7.23-7.13 (m, 3H), 7.05 (br d, J = 7.9 Hz, 2H),6.98 (d, J = 7.9 Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H), 4.69 (s, 2H), 3.99(br t, J = 6.9 Hz, 2H), 3.80-3.75 (m, 1H), 3.74-3.69 (m, 1H), 2.37 (t, J= 7.3 Hz, 2H), 2.18 (dt, J = 12.4, 7.9 Hz, 1H), 2.04-1.98 (m, 1H),1.56-1.48 (m, 2H), 1.29 (dq, J = 14.9, 7.3 Hz, 2H), 0.82 (t, J = 7.3 Hz,3H). 152

520.6 521.2; 1.84 min; 99% (Method A2) 7.82 (br d, J = 7.0 Hz, 1H),7.76- 7.69 (m, 2H), 7.63 (s, 1H), 7.59 (br d, J = 7.9 Hz, 1H), 7.40 (t,J = 7.6 Hz, 1H), 7.25 (br d, J = 7.3 Hz, 1H), 7.21 (br d, J = 8.2 Hz,2H), 7.12 (br d, J = 7.9 Hz, 2H), 4.72 (s, 2H), 4.00 (br t, J = 6.7 Hz,2H), 3.80-3.75 (m, 1H), 3.75- 3.69 (m, 1H), 2.41 (s, 3H), 2.36 (br t, J= 7.3 Hz, 2H), 2.19 (dt, J = 12.4, 7.9 Hz, 1H), 2.01 (dt, J = 12.1, 6.0Hz, 1H), 1.52 (quin, J = 7.5 Hz, 2H), 1.30 (sxt, J = 7.4 Hz, 2H), 0.83(t, J = 7.3 Hz, 3H) 153

520.6 521.3; 1.80 min; 100% (Method A2) 7.84 (br d, J = 7.6 Hz, 1H),7.78- 7.70 (m, 2H), 7.65 (s, 1H), 7.61 (br d, J = 7.6 Hz, 1H), 7.41 (t,J = 7.5 Hz, 1H), 7.26 (br d, J = 7.3 Hz, 1H), 7.22 (br d, J = 7.6 Hz,2H), 7.13 (br d, J = 7.9 Hz, 2H), 4.73 (s, 2H), 4.01 (br t, J = 6.7 Hz,2H), 3.82-3.76 (m, 1H), 3.75- 3.70 (m, 1H), 2.42 (s, 3H), 2.37 (br t, J= 7.5 Hz, 2H), 2.19 (dt, J = 12.4, 7.9 Hz, 1H), 2.02 (dt, J = 12.0, 5.8Hz, 1H), 1.53 (quin, J = 7.5 Hz, 2H), 1.35-1.26 (m, 2H), 0.84 (t, J =7.3 Hz, 3H)

Example 154:2-butyl-3-((5′-(4-methylpyridin-2-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 154a:4′-((2-butyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 146e-enantiomer 1 (140 mg, 0.30 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (99 mg, 0.39mmol), KOAc (74 mg, 0.75 mmol) in dioxane (2 mL) was degassed bybubbling Ar for 1 min, then Pd (dppf)Cl₂ complex with CH₂Cl₂ (1:1) (12mg, 0.015 mmol) was added. The mixture was sealed in a pressure vial andheated in an oil bath at 125° C. for 1 h. The reaction mixture wasdirectly loaded onto a silica gel cartridge, purified by flashchromatography (0% to 15% MeOH in CH₂Cl₂ over 12 min using a 12 g silicagel cartridge). The desired fractions were combined, concentrated andlyophilized to yield Intermediate 154a (123 mg, 0.24 mmol, 80% yield) assolid. 1H NMR (500 MHz, CDCl₃) δ 7.93 (s, 1H), 7.88 (d, J=7.7 Hz, 1H),7.82-7.75 (m, 1H), 7.60 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H),4.83-4.74 (m, 2H), 4.27-4.16 (m, 2H), 4.03-3.99 (m, 1H), 3.96-3.92 (m,1H), 2.45-2.38 (m, 3H), 2.23-2.16 (m, 1H), 1.67 (br t, J=7.6 Hz, 2H),1.38 (s, 12H), 0.92 (t, J=7.3 Hz, 3H). LC-MS (Method A2): RT=0.70 min,MS (ESI) m/z: 432.1 (M+H)⁺.

Intermediate 154b:4′-((2-butyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

A solution of Intermediate 154a (37 mg, 0.073 mmol),2-bromo-4-methylpyridine (25 mg, 0.15 mmol) and Pd-XPhos G3 (2.5 mg, 2.9mol) in THF (1.5 mL) and K₃PO₄ (1.0 M, 0.15 mL, 0.15 mmol) was degassedwith Ar for 1 min. The reaction mixture was sealed in a pressure vialand heated at 120° C. in a microwave reactor for 45 min. LC-MS indicatedcompletion of reaction. The reaction mixture was concentrated andpurified by column chromatography (0% to 15% MeOH in CH₂Cl₂ over 10 minusing a 4 g silica gel cartridge). The desired fractions were combinedand further purified by preparative HPLC (method E) to yieldIntermediate 154b (20 mg, 0.042 mmol, 58% yield) as a white lyophilate.LC-MS (Method A2): RT=0.75 min, MS (ESI) m/z: 479.0 (M+H)⁺.

Example 154

Intermediate 154b (20 mg, 0.042 mmol) was dissolved in toluene (836 μl).Bu₂SnO (26 mg, 0.10 mmol) and TMS-N₃ (83 μl, 0.63 mmol) were added, andthe reaction sealed in a pressure vial and heated at 105° C. overnight.LC-MS indicated completion of reaction. Toluene was removed by blowing aslow stream of Na. The mixture was purified by preparative HPLC (methodG) to yield Example 154 (7.3 mg, 0.011 mmol, 26.7% yield). ¹H NMR (500MHz, DMSO-d₆) δ 8.59 (d, J=5.2 Hz, 1H), 8.28 (br d, J=7.9 Hz, 1H), 8.22(s, 1H), 8.07 (s, 1H), 7.82 (d, J=8.2 Hz, 1H), 7.33 (br d, J=4.9 Hz,1H), 7.25 (s, 1H), 7.23-7.16 (m, 4H), 7.15 (s, 1H), 7.05 (s, 1H), 4.76(s, 2H), 4.01 (t, J=6.7 Hz, 2H), 3.81-3.75 (m, 1H), 2.45 (s, 3H), 2.41(br t, J=7.6 Hz, 2H), 2.21 (dt, J=12.6, 7.7 Hz, 1H), 2.10-2.02 (m, 1H),1.53 (quin, J=7.5 Hz, 2H), 1.30 (dq, J=14.9, 7.3 Hz, 2H), 0.84 (t, J=7.3Hz, 3H). LC-MS (Method A2): RT=1.0 min, MS (ESI) m/z: 522.0 (M+H)⁺.Analytical HPLC purity (Method A2): 97%.

Example 155:2-butyl-3-03″-methyl-6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-one

Intermediate 155a: 4-aminotetrahydro-2H-pyran-4-carbonitrilehydrochloride

To a solution of tetrahydro-4H-pyran-4-one (1.3 g, 13 mmol) in MeOH (4mL) was added 7N ammonia/MeOH (3.71 mL, 26.0 mmol) at rt. The mixturewas cooled with an ice bath and AcOH (0.82 mL, 14.28 mmol) was addeddropwise. The mixture was stirred at rt for 10 min then NaCN (0.636 g,12.98 mmol) was added in one portion. The mixture was heated up to 50°C. in oil bath for 2 h and rt overnight. The mixture was concentrated,EtOAc was added to the concentrated mixture and stir for 15 min. Theslurry was removed by filtration and the wet cake was washed with EtOActwice. The combined filtrates were concentrated and the crude sample wasresolved in DCM (20 mL) and treated with 4N HCl in dioxane (4.87 mL,19.48 mmol) at rt for 15 min Precipitation was formed and the mixturewas concentrated. The residual was triturated in ether. The titlecompound (Intermediate 155a, 2.1 g, 12.91 mmol, 99% yield) was obtainedby filtration as an off-white solid. ¹H NMR (500 MHz, MeOH-d₄) δ 4.13(dd, J=12.7, 4.7 Hz, 2H), 3.71-3.63 (m, 2H), 2.24 (dd, J=12.9, 1.4 Hz,2H), 2.08-1.91 (m, 2H).

Intermediate 155b: N-(4-cyanotetrahydro-2H-pyran-4-yl)pentanamide

To a solution of 4-aminotetrahydro-2H-pyran-4-carbonitrile hydrochloride(155a, 230 mg, 1.414 mmol) in DCM (4 mL) was added potassium carbonate(1016 mg, 7.35 mmol) in H₂O (4 mL). The mixture was cooled with an icebath. Pentanoyl chloride (0.235 mL, 1.980 mmol) in DCM (4 mL) was addeddropwise to the stirred solution. The reaction mixture was stirred at 0°C. for 2 h, and at rt for 3 h. The organic phase was collected. Theaqueous phase was extracted (2×) with DCM. The combined organic phasewas washed with brine, dried over Na₂SO₄ and concentrated. The residuewas purified by ISCO (Hexanes/AcOEt, 0-100%) to give the title compound(Intermediate 155b, 240 mg, 1.141 mmol, 81% yield) as oil. LC-MS (MethodA5): 1.63 min, [M+H]⁺=221.1; ¹H NMR (500 MHz, MeOH-d₄) δ 8.43 (br s,1H), 3.91 (dt, J=12.6, 4.0 Hz, 2H), 3.72 (ddd, J=12.4, 10.1, 2.5 Hz,2H), 2.33 (dt, J=13.5, 1.9 Hz, 2H), 2.26 (t, J=7.4 Hz, 2H), 1.93 (ddd,J=13.8, 10.0, 4.0 Hz, 2H), 1.74-1.56 (m, 2H), 1.46-1.29 (m, 2H), 0.96(t, J=7.4 Hz, 3H).

Intermediate 155c: 2-butyl-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-onehydrochloride

To a solution of N-(4-cyanotetrahydro-2H-pyran-4-yl)pentanamide(Intermediate 155b, 160 mg, 0.761 mmol) in n-propanol (2 mL) was added4N HCl in dioxane (1.902 mL, 7.61 mmol) dropwise. The mixture was heatedup to 50° C. in oil bath for overnight. The mixture was concentrated anddried under vacuum to give the title compound (Intermediate 155c, 188mg, 0.761 mmol, 100% yield) as a whit solid. LC-MS (Method A5): 0.91min, [M+H]⁺=221.1; ¹H NMR (500 MHz, MeOH-d₄) δ 4.16-3.93 (m, 2H),3.86-3.73 (m, 2H), 2.99-2.70 (m, 2H), 2.18-2.03 (m, 2H), 1.90 (br dd,J=7.6, 4.0 Hz, 2H), 1.86-1.75 (m, 2H), 1.55-1.45 (m, 2H), 1.04 (t, J=7.4Hz, 3H).

Intermediate 155d:5-bromo-4′-((2-butyl-4-oxo-8-oxa-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)biphenyl-2-carbonitrile

2-butyl-8-oxa-1, 3-diazaspiro[4.5]dec-1-en-4-one, HCl (Intermediate155c, 260 mg, 1.054 mmol) was dissolved in DMF (5 mL). NaH (105 mg, 2.63mmol) was added. The mixture was stirred at rt for 15 min,5-bromo-4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (1-002, 388 mg,1.106 mmol) was added at 0° C. The reaction mixture was stirred at rtfor 1 h. The reaction mixture was diluted with EtOAc, washed withsaturated NH₄Cl, brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by ISCO (Hexanes/AcOEt, 0-100%) to givethe title compound (Intermediate 155d, 383 mg, 0.797 mmol, 76% yield) asoff white solid. LC-MS (Method A5): 2.44 min, [M+H]⁺=480.1 and 482.1; ¹HNMR (500 MHz, CDCl₃) δ 7.68 (d, J=1.1 Hz, 1H), 7.66-7.58 (m, 2H), 7.55(d, J=8.3 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H), 4.77 (s, 2H), 4.09-4.02 (m,2H), 4.01-3.94 (m, 2H), 2.45-2.35 (m, 2H), 2.11-1.99 (m, 2H), 1.64 (dt,J=15.1, 7.6 Hz, 2H), 1.50 (br d, J=13.5 Hz, 2H), 1.42-1.35 (m, 2H), 0.91(t, J=7.3 Hz, 3H).

Intermediate 155e:4″-((2-butyl-4-oxo-8-oxa-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-3-methyl[1,1′:3′,1″-terphenyl]-4′-carbonitrile

A mixture of5-bromo-4′-((2-butyl-4-oxo-8-oxa-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(Intermediate 155d, 25 mg, 0.052 mmol) and m-tolylboronic acid (21.23mg, 0.156 mmol) in THF (1 mL) was treated with 1.5 M Na₂CO₃ (0.104 mL,0.156 mmol) followed by PdCl₂(dppf) (4.25 mg, 5.20 mol). The resultingmixture was degassed with N₂ for 2 min before the reaction vessel wassealed and irradiated in a microwave reactor at 120° C. for 30 min. Thecooled reaction mixture was concentrated to dryness and the residuepurified by ISCO (Hexanes/AcOEt, 0-100%) to afford the title compound(Intermediate 155e, 25 mg, 0.051 mmol, 98% yield) as an amber oil. LC-MS(Method A5): 2.57 min, [M+H]⁺=492.2; ¹H NMR (500 MHz, CDCl₃) δ 7.84 (d,J=8.0 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.70-7.65 (m, 1H), 7.62 (d, J=8.0Hz, 2H), 7.44 (d, J=7.2 Hz, 2H), 7.42-7.37 (m, 1H), 7.33 (d, J=8.0 Hz,2H), 7.29-7.26 (m, 1H), 4.78 (s, 2H), 4.09-4.03 (m, 2H), 4.02-3.95 (m,2H), 2.46 (s, 3H), 2.44-2.39 (m, 2H), 2.11-2.02 (m, 2H), 1.71-1.59 (m,2H), 1.52 (br d, J=13.2 Hz, 2H), 1.40 (sxt, J=7.4 Hz, 2H), 0.92 (t,J=7.3 Hz, 3H).

Example 155:2-butyl-3-((3″-methyl-6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-one

To a solution of4″-((4-oxo-2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile(Intermediate 155e, 24 mg, 0.051 mmol) in toluene (1.5 mL) was addeddibutyltin oxide (25.3 mg, 0.102 mmol) and TMS-N₃ (0.067 mL, 0.509mmol). Then the reaction vessel was sealed and the mixture was heated at100° C. overnight behind a blast shield (according to the proceduredescribed in J. Org. Chem, 1993, 58, 4139). After cooling, the reactionmixture was concentrated, re-solvated in DMF, filtered then purified viapreparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂Owith 10 mM NH₄OAc; Gradient: 24-64% B over 20 minutes, then a 4-minutehold at 100% B; Flow: 20 mL/min) to afford 14.1 mg (0.026 mmol, 51.9%yield) of the title compound Example 155. LC-MS (Method A3): 1.41 min,[M+H]⁺=535.25; NMR (500 MHz, DMSO-d₆) δ 7.84-7.76 (m, 1H), 7.75-7.70 (m,1H), 7.66 (d, J=1.4 Hz, 1H), 7.59 (s, 1H), 7.56 (br d, J=7.7 Hz, 1H),7.38 (t, J=7.6 Hz, 1H), 7.23 (br d, J=7.6 Hz, 1H), 7.20 (br d, J=8.0 Hz,2H), 7.08 (br d, J=8.1 Hz, 2H), 4.69 (s, 2H), 3.99-3.84 (m, 2H),3.82-3.73 (m, 2H), 2.40 (s, 3H), 2.35 (t, J=7.5 Hz, 2H), 1.89-1.76 (m,2H), 1.52 (quin, J=7.3 Hz, 2H), 1.39-1.24 (m, 4H), 0.82 (t, J=7.3 Hz,3H).

The following examples have been similarly prepared from Intermediate155d as described above for Example 155. Two analytical LC-MS injectionswere used to determine the final purity. The retention time of one ofthem is reported for each compound and is referred as Method A3, MethodA4 or Method A5.

LC-MS m/z [M + H]⁺; ¹H NMR RT; (500 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 156

520.64 521.06; 1.53 min (Method A3) 7.85-7.76 (m, 3H), 7.74 (d, J = 7.9Hz, 1H), 7.70 (s, 1H), 7.55- 7.48 (m, 2H), 7.46-7.40 (m, 1H), 7.20 (d, J= 7.9 Hz, 2H), 7.09 (br d, J = 7.9 Hz, 2H), 4.71 (s, 2H), 3.88 (br d, J= 11.3 Hz, 2H), 3.83- 3.68 (m, 2H), 2.52 (br s, 6H), 2.36 (t, J = 7.5Hz, 2H), 1.87-1.77 (m, 2H), 1.57-1.43 (m, 2H), 1.40- 1.20 (m, 4H), 0.82(t, J = 7.3 Hz, 3H). 157

536.64 537.13; 1.34 (Method A3) 7.64 (s, 2H), 7.57 (s, 1H), 7.37 (br d,J = 7.6 Hz, 1H), 7.23-7.18 (m, 1H), 7.16 (br d, J = 8.0 Hz, 2H), 7.05(br d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.1 Hz, 1H), 6.91 (t, J = 7.5 Hz,1H), 4.68 (s, 2H), 3.92-3.84 (m, 2H), 3.82-3.72 (m, 2H), 2.35 (br t, J =7.5 Hz, 2H), 1.87-1.72 (m, 2H), 1.51 (dt, J = 14.7, 7.4 Hz, 2H),1.38-1.21 (m, 4H), 0.81 (t, J = 7.3 Hz, 3H)

Example 158-enantiomer 1:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 158a: 3-aminotetrahydrofuran-3-carbonitrile hydrochloride

To a solution of dihydrofuran-3(2H)-one (0.8 g, 9.29 mmol) in MeOH (4mL) was added 7N ammonia/MeOH (2.66 mL, 18.59 mmol) at rt. The mixturewas cooled with an ice bath and AcOH (0.585 mL, 10.22 mmol) was addeddropwise. The mixture was stirred at rt for 10 min then NaCN (0.455 g,9.29 mmol) was added in one portion. The mixture was heated up to 50° C.in oil bath for 2 h and rt for overnight. The mixture was concentrated,EtOAc was added to the concentrated mixture and stir for 15 min. Theslurry was removed by filtration and the wet cake was washed with EtOAcfor 2 times. The combined filtrates were concentrated and the crudesample was resolved in DCM (20 mL) and treated with 4N HCl in dioxane(3.48 mL, 13.94 mmol) at rt for 15 min. Precipitation was formed and themixture was concentrated. The residual was triturated in ether. Thetitle compound (Intermediate 158a, 1.30 g, 8.92 mmol, 96% yield) wasobtained by filtration as an off-white solid. ¹H NMR (500 MHz, MeOH-d₄)δ 4.22-4.14 (m, 2H), 4.13-4.09 (m, 1H), 4.02 (td, J=8.9, 6.6 Hz, 1H),2.80 (ddd, J=14.2, 8.7, 5.5 Hz, 1H), 2.46 (dt, J=14.4, 7.3 Hz, 1H).

Intermediate 158b: N-(3-cyanotetrahydrofuran-3-yl)butyramide

To a solution of 3-aminotetrahydrofuran-3-carbonitrile, HCl(Intermediate 158a, 400 mg, 2.69 mmol) in DCM (8 mL) was added potassiumcarbonate (1935 mg, 14.00 mmol) in H₂O (8 mL). The mixture was cooledwith an ice bath, butyryl chloride (0.394 mL, 3.77 mmol) in DCM (4 mL)was added dropwise to the stirred solution. The reaction mixture wasstirred at 0° C. for 2 h, and at rt for 3 h. The organic phase wascollected. The aqueous phase was extracted (2×) with DCM. The combinedorganic phase was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified by ISCO (Hexanes/AcOEt, 0-100%) to give thetitle compound (Intermediate 158b, 410 mg, 2.250 mmol, 84% yield) asoil. LC-MS (Method A5): 0.92 min, [M+H]⁺=183.1; ¹H NMR (500 MHz,MeOH-d₄) δ 4.24 (d, J=9.4 Hz, 1H), 4.05-3.98 (m, 1H), 3.98-3.92 (m, 2H),2.69-2.55 (m, 1H), 2.50-2.36 (m, 1H), 2.28-2.12 (m, 2H), 1.76-1.58 (m,2H), 1.04-0.85 (m, 3H).

Intermediate 158c: 2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-onehydrochloride

To a solution of N-(3-cyanotetrahydrofuran-3-yl)butyramide (Intermediate158b, 410 mg, 2.250 mmol) in n-propanol (6 mL) was added 4N HCl indioxane (5.62 mL, 22.50 mmol) dropwise. The mixture was heated up to 50°C. in oil bath for overnight. The mixture was concentrated and driedunder vacuum to give the title compound (Intermediate 158c, 492 mg,2.250 mmol, 100% yield) as a white solid. LC-MS (Method A5): 0.40 min,[M+H]⁺=221.1; ¹H NMR (500 MHz, MeOH-d₄) δ 4.23-4.12 (m, 2H), 4.11-4.00(m, 1H), 3.93 (d, J=10.2 Hz, 1H), 2.85 (t, J=7.7 Hz, 2H), 2.62-2.49 (m,1H), 2.41 (dt, J=13.7, 6.8 Hz, 1H), 1.98-1.74 (m, 2H), 1.11 (t, J=7.4Hz, 3H).

Intermediate 158d:5-bromo-4′-((4-oxo-2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile

2-Propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-one, HCl (Intermediate158c, 492 mg, 2.25 mmol) was dissolved in DMF (10 mL). NaH (225 mg, 5.63mmol) was added. The mixture was stirred at rt for 15 min,5-bromo-4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (1-002, 829 mg,2.363 mmol) was added at 0° C. The reaction mixture was stirred at rtfor 1 h. The reaction mixture was diluted with EtOAc, washed withsaturated NH₄C₁, brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by ISCO (Hexanes/AcOEt, 0-100%) to givethe title compound (Intermediate 158d, 620 mg, 1.371 mmol, 60.9% yield)as as a white solid. LC-MS (Method A5): 2.30 min, [M+H]⁺=452.1 and454.1; ¹H NMR (500 MHz, CDCl₃) δ 7.70 (d, J=1.1 Hz, 1H), 7.67-7.62 (m,2H), 7.56 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H), 4.78 (d, J=6.6 Hz,2H), 4.27-4.17 (m, 2H), 4.05-3.97 (m, 1H), 3.96-3.89 (m, 1H), 2.50-2.32(m, 3H), 2.18 (ddd, J=12.3, 6.8, 5.4 Hz, 1H), 1.79-1.63 (m, 2H), 0.99(t, J=7.4 Hz, 3H).

Intermediate 158e-enantiomer 1:5-bromo-4′-((4-oxo-2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile

Intermediate 158d-racemate (620 mg, 1.371 mmol) were resolved into twopeaks on Instrument PIC Solution SFC Prep-200 with the followingpreparative chromatographic conditions: Column: Chiralpak AD-H, 30×250mm, 5 micron; Mobile Phase: 20% IPA/80% CO₂; Flow Conditions: 85 mL/min,120 Bar, 40° C.; Detector Wavelength: 220 nm; injection details: 0.5 mLof ˜155 mg/mL in IPA/ACN. Purity of each fraction was determined usingthe analytical chromatographic condition below: Instrument: AuroraAnalytical SFC; Column: Chiralpak AD-H, 4.6×250 mm, 5 micron; MobilePhase: 20% IPA/80% CO₂; Flow Conditions: 2.0 mL/min, 150 Bar, 40° C.;Detector Wavelength: 220 nm; Injection Details: 10 μL of ˜0.2 mg/mL inMeOH.

Peak 1 was collected and concentrated to give Intermediate158e-enantiomer 1 (200 mg, 0.44 mmol, 32% yield): enantiomericexcess >99%. Chiral analytical RT=7.75 min. LC-MS (Method A5): 2.30 min,[M+H]⁺=452.1 and 454.1; ¹H NMR (500 MHz, CDCl₃) δ 7.70 (d, J=1.4 Hz,1H), 7.68-7.60 (m, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H),4.78 (d, J=6.6 Hz, 2H), 4.28-4.09 (m, 2H), 4.03-3.98 (m, 1H), 3.96-3.91(m, 1H), 2.52-2.28 (m, 3H), 2.18 (ddd, J=12.3, 6.9, 5.2 Hz, 1H),1.76-1.65 (m, 2H), 0.99 (t, J=7.3 Hz, 3H).

Intermediate 158f-enantiomer 2:5-bromo-4′-((4-oxo-2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile

Peak 2 was collected and concentrated to give Intermediate158f-enantiomer 2 (200 mg, 0.44 mmol, 32% yield): enantiomeric excess:94%. Chiral analytical RT=10.01 min. LC-MS (Method A5): 2.30 min,[M+H]⁺=452.1 and 454.1; ¹H NMR (500 MHz, CDCl₃) δ 7.68 (d, J=1.4 Hz,1H), 7.64-7.60 (m, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.31 (d, J=8.0 Hz, 2H),4.77 (d, J=6.3 Hz, 2H), 4.26-4.11 (m, 2H), 3.99 (d, J=8.8 Hz, 1H),3.94-3.86 (m, 1H), 2.49-2.31 (m, 3H), 2.16 (ddd, J=12.3, 6.7, 5.5 Hz,1H), 1.83-1.64 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).

Intermediate 158 g:4″-((4-oxo-2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

A mixture of5-bromo-4′-((4-oxo-2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile(Intermediate 158e, 25 mg, 0.055 mmol) and phenylboronic acid (10.11 mg,0.083 mmol) in THF (1 mL) was treated with 1.5 M Na₂CO₃ (0.111 mL, 0.166mmol) followed by PdCl₂(dppf) (4.51 mg, 5.53 μmol). The resultingmixture was degassed with N₂ for 2 min before the reaction vessel wassealed and irradiated in a microwave reactor at 120° C. for 30 min. Thecooled reaction mixture was concentrated to dryness and the residuepurified by ISCO (Hexanes/AcOEt, 0-100%) to afford the title compound(Intermediate 158 g, 24 mg, 0.055 mmol, 100% yield) as an amber oil.LC-MS (Method A5): 2.46 min, [M+H]⁺=450.2; ¹H NMR (500 MHz, CDCl₃) δ7.84 (d, J=8.0 Hz, 1H), 7.70 (d, J=1.4 Hz, 1H), 7.70-7.65 (m, 1H), 7.62(d, J=8.0 Hz, 2H), 7.44 (d, J=7.2 Hz, 2H), 7.42-7.37 (m, 1H), 7.33 (d,J=8.0 Hz, 2H), 7.29-7.26 (m, 1H), 4.78 (s, 2H), 4.09-4.03 (m, 2H),4.02-3.95 (m, 2H), 2.46 (s, 3H), 2.44-2.39 (m, 2H), 2.11-2.02 (m, 2H),1.71-1.59 (m, 2H), 1.52 (br d, J=13.2 Hz, 2H), 1.40 (sxt, J=7.4 Hz, 2H),0.92 (t, J=7.3 Hz, 3H).

Example 158-enantiomer 1:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-one

To a solution of4″-((4-oxo-2-propyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile(Intermediate 158 g, 24 mg, 0.055 mmol) in toluene (1.5 mL) was addeddibutyltin oxide (27.7 mg, 0.111 mmol) and TMS-N₃ (0.074 mL, 0.556mmol). Then the reaction vessel was sealed and the mixture was heated at100° C. overnight behind a blast shield (according to the proceduredescribed in J. Org. Chem, 1993, 58, 4139). After cooling, the reactionmixture was concentrated, re-solvated in DMF, filtered then purified viapreparative HPLC for two times (First: Column: XBridge C18, 19×200 mm,5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; MobilePhase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 6-52% B over 20minutes, then a 4-minute hold at 100% B; Flow: 20 mL/min; Second: ColumnXBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂Owith 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc;Gradient: 11-51% B over 20 minutes, then a 4-minute hold at 100% B;Flow: 20 mL/min) to afford 8.0 mg (0.016 mmol, 29.2% yield) of the titlecompound Example 158-enantiomer 1. LC-MS (Method A3): 1.38 min,[M+H]⁺=493.18; ¹H NMR (500 MHz, DMSO-d₆) δ 7.78 (br d, J=7.4 Hz, 2H),7.74 (s, 2H), 7.64 (s, 1H), 7.50 (br t, J=7.7 Hz, 2H), 7.45-7.34 (m,1H), 7.23 (br d, J=8.0 Hz, 2H), 7.08 (br d, J=7.9 Hz, 2H), 4.70 (s, 2H),4.01 (t, J=6.8 Hz, 2H), 3.82-3.70 (m, 2H), 2.36 (t, J=7.2 Hz, 2H), 2.19(dt, J=12.3, 7.7 Hz, 1H), 2.09-1.98 (m, 1H), 1.67-1.55 (m, 2H), 0.91 (t,J=7.4 Hz, 3H).

The following examples have been similarly prepared from Intermediate158e-enantiomer 1 as described above for Example 158-enantiomer 1. Twoanalytical LC-MS injections were used to determine the final purity. Theretention time of one of them is reported for each compound and isreferred as Method A3, Method A4 or Method A5.

LC-MS m/z [M + H]⁺; ¹H NMR (500 MHz, DMSO-d₆) Ex Structure MW RT;(Method) δ ppm 159

506.61 507.03; 1.5 min (Method A3) 7.79-7.69 (m, 2H), 7.64 (d, J = 1.4Hz, 1H), 7.59 (s, 1H), 7.55 (br d, J = 7.7 Hz, 1H), 7.38 (t, J = 7.6 Hz,1H), 7.26-7.17 (m, 3H), 7.08 (br d, J = 8.0 Hz, 2H), 4.69 (s, 2H), 4.00(dd, J = 7.6, 6.0 Hz, 2H), 3.82-3.66 (m, 2H), 2.39 (s, 3H), 2.38-2.29(m, 2H), 2.18 (dt, J = 12.4, 7.8 Hz, 1H), 2.02 (td, J = 11.8, 5.4 Hz,1H), 1.73-1.50 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H) 160

508.58 509.01; 1.19 min (Method A3) 7.65 (s, 2H), 7.58 (s, 1H), 7.38 (brd, J = 6.9 Hz, 1H), 7.26-7.13 (m, 3H), 7.07 (br d, J = 7.7 Hz, 2H), 6.98(d, J = 8.0 Hz, 1H), 6.91 (br t, J = 7.4 Hz, 1H), 4.69 (s, 2H),4.05-3.96 (m, 2H), 3.80-3.68 (m, 2H), 2.34 (br t, J = 7.2 Hz, 2H),2.23-2.15 (m, 1H), 2.07-1.97 (m, 1H), 1.58 (br dd, J = 14.6, 7.4 Hz,2H), 0.88 (q, J = 7.2 Hz, 3H) 161

510.57 511.01; 1.38 min (Method A3) 7.72 (d, J = 7.9 Hz, 1H), 7.69-7.61(m, 2H), 7.55 (s, 1H), 7.52-7.41 (m, 1H), 7.40-7.30 (m, 2H), 7.17 (br d,J = 7.9 Hz, 2H), 7.07 (br d, J = 7.9 Hz, 2H), 4.69 (s, 2H), 3.99 (br t,J = 6.7 Hz, 2H), 3.86-3.66 (m, 2H), 2.33 (br t, J = 7.2 Hz, 2H), 2.17(dt, J = 12.4, 7.8 Hz, 1H), 2.01 (dt, J = 12.1, 5.9 Hz, 1H), 1.64-1.46(m, 2H), 0.87 (t, J = 7.3 Hz, 3H)

The following examples have been similarly prepared from Intermediate158f-enantiomer 2 as described above for Example 158. Two analyticalLC-MS injections were used to determine the final purity. The retentiontime of one of them is reported for each compound and is referred asMethod A3, Method A4 or Method A5.

LC-MS m/z [M + H]⁺; ¹H NMR (500 MHz, DMSO-d₆) Ex Structure MW RT;(Method) δ ppm 162

492.58 493.32; 1.34 min (Method A3) 7.77 (br d, J = 7.6 Hz, 2H), 7.72(s, 2H), 7.62 (s, 1H), 7.49 (br t, J = 7.4 Hz, 2H), 7.44-7.34 (m, 1H),7.22 (br d, J = 7.9 Hz, 2H), 7.07 (br d, J = 7.7 Hz, 2H), 4.69 (s, 2H),4.00 (br t, J = 6.7 Hz, 2H), 3.84-3.63 (m, 2H), 2.36 (br t, J = 7.2 Hz,2H), 2.19 (dt, J = 12.2, 7.8 Hz, 1H), 2.07-1.95 (m, 1H), 1.67-1.46 (m,2H), 0.90 (br t, J = 7.3 Hz, 3H) 163

506.61 507.4; 1.73 min (Method A3) 7.79-7.66 (m, 2H), 7.62 (br d, J =10.1 Hz, 2H), 7.57 (br d, J = 7.3 Hz, 1H), 7.41-7.35 (m, 1H), 7.38 (t, J= 7.8 Hz, 1H), 7.25-7.18 (m, 3H), 7.07 (br d, J = 8.2 Hz, 2H), 4.70 (s,2H), 4.00 (br t, J = 6.7 Hz, 2H), 3.79-3.70 (m, 2H), 2.40 (s, 3H), 2.36(br t, J = 7.3 Hz, 2H), 2.25-2.14 (m, 1H), 2.06-1.96 (m, 1H), 1.65-1.54(m, 2H), 0.90 (t, J = 7.3 Hz, 3H) 164

508.58 509.01; 1.18 min (Method A3) 7.76 (br s, 1H), 7.68 (br s, 2H),7.41 (br d, J = 7.6 Hz, 1H), 7.23 (br t, J = 7.6 Hz, 1H), 7.13 (br s,4H), 6.99 (d, J = 8.2 Hz, 1H), 6.93 (br t, J = 7.5 Hz, 1H), 4.70 (s,2H), 3.99 (br t, J = 6.6 Hz, 2H), 3.81- 3.68 (m, 2H), 2.32 (br t, J =7.2 Hz, 2H), 2.18 (dt, J = 12.2, 7.6 Hz, 1H), 2.01 (dt, J = 11.8, 5.8Hz, 1H), 1.61-1.49 (m, 2H), 0.88- 0.84 (m, 3H)

Example 165:4″-((2-ethyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

Intermediate 165a: N-(3-cyanotetrahydrofuran-3-yl)propionamide

To a solution of Intermediate 158a (600 mg, 4.04 mmol) in DCM (10 mL)was added potassium carbonate (2902 mg, 21.00 mmol) in H₂O (10 mL). Themixture was cooled with an ice bath, ropionyl chloride (523 mg, 5.65mmol) in DCM (4 mL) was added dropwise to the stirred solution. Thereaction mixture was stirred at 0° C. for 2 h, and at rt for 3 h. Theorganic phase was collected. The aqueous phase was extracted (2×) withDCM. The combined organic phase was washed with brine, dried over Na₂SO₄and concentrated. The residue was purified by ISCO (Hexanes/AcOEt,0-100%) to give the title compound (Intermediate 165a, 500 mg, 2.97mmol, 73.6% yield) as oil. LC-MS (Method A5): 0.39 min, [M+H]⁺=169.1; ¹HNMR (500 MHz, MeOH-d₄) δ 9.37 (br s, 1H), 4.80 (d, J=9.4 Hz, 1H),4.61-4.43 (m, 3H), 3.18 (ddd, J=13.3, 7.6, 6.9 Hz, 1H), 3.05 (ddd,J=13.3, 7.5, 5.9 Hz, 1H), 2.82 (q, J=7.7 Hz, 2H), 1.63 (t, J=7.6 Hz, 3H)

Intermediate 165b: 2-ethyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-onehydrochloride

To a solution of Intermediate 165a (500 mg, 2.97 mmol) in n-propanol(7.5 mL) was added 4N HCl in dioxane (7.43 mL, 29.7 mmol) dropwise. Themixture was heated up to 50° C. in oil bath for overnight. The mixturewas concentrated and dried under vacuum to give the title compound(Intermediate 165b, 600 mg, 2.93 mmol, 99% yield) as a whit solid. LC-MS(Method A5): 0.28 min, [M+H]⁺=169.1; ¹H NMR (500 MHz, MeOH-d₄) δ4.77-4.72 (m, 2H), 4.65-4.61 (m, 1H), 4.53 (d, J=9.9 Hz, 1H), 3.57 (q,J=7.4 Hz, 2H), 3.11-2.99 (m, 1H), 2.94 (dt, J=13.4, 8.0 Hz, 1H), 1.98(t, J=7.6 Hz, 3H).

Intermediate 165c:5-bromo-4′-((2-ethyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile

Intermediate 165b (400 mg, 1.954 mmol) was dissolved in DMF (10 mL). NaH(176 mg, 4.40 mmol) was added. The mixture was stirred at rt for 15 min,5-bromo-4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (1-002, 720 mg,2.052 mmol) was added at 0° C. The reaction mixture was stirred at rtfor 1 h. The reaction mixture was diluted with EtOAc, washed withsaturated NH₄C₁, brine, dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by ISCO (DCM/AcOEt, 0-100%) to give thetitle compound (Intermediate 165c, 450 mg, 1.027 mmol, 52.5% yield) as awhite solid. LC-MS (Method A5): 2.29 min, [M+H]⁺=438.1 and 440.1; ¹H NMR(500 MHz, MeOH-d₄) δ 7.76 (d, J=1.4 Hz, 1H), 7.73-7.69 (m, 2H), 7.58 (d,J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 4.85 (d, J=5.0 Hz, 2H), 4.23-4.12(m, 2H), 4.00-3.93 (m, 1H), 3.92-3.80 (m, 1H), 2.51 (q, J=7.2 Hz, 2H),2.37 (dt, J=12.7, 7.7 Hz, 1H), 2.17 (ddd, J=12.4, 6.9, 5.4 Hz, 1H), 1.20(t, J=7.4 Hz, 3H).

Intermediate 165d-enantiomer 1:5-bromo-4′-((2-ethyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile

Intermediate 165c-racemate (450 mg, 1.027 mmol) were resolved into twopeaks on Instrument PIC Solution SFC Prep-200 with the followingpreparative chromatographic conditions: Column: Chiralpak AD-H, 30×250mm, 5 micron; Mobile Phase: 20% IPA/80% CO₂; Flow Conditions: 85 mL/min,120 Bar, 40° C.; Detector Wavelength: 220 nm; injection details: 0.5 mLof ˜155 mg/mL in IPA/MeOH. Purity of each fraction was determined usingthe analytical chromatographic condition below: Instrument: AuroraAnalytical SFC; Column: Chiralpak AD-H, 4.6×250 mm, 5 micron; MobilePhase: 20% IPA/80% CO₂; Flow Conditions: 2.0 mL/min, 150 Bar, 40° C.;Detector Wavelength: 220 nm; Injection Details: 10 μL of ˜0.2 mg/mL inMeOH.

Peak 1 was collected and concentrated to give Intermediate165d-enantiomer 1 (100 mg, 0.23 mmol, 22% yield): enantiomericexcess >99%. Chiral analytical RT=8.72 min LC-MS (Method A5): 2.29 min,[M+H]⁺=438.1 and 440.1; ¹H NMR (500 MHz, CDCl₃) δ 7.69 (d, J=1.1 Hz,1H), 7.67-7.60 (m, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.33 (d, J=8.3 Hz, 2H),4.78 (d, J=6.6 Hz, 2H), 4.30-4.12 (m, 2H), 4.02-3.97 (m, 1H), 3.96-3.85(m, 1H), 2.55-2.28 (m, 3H), 2.19 (ddd, J=12.4, 6.9, 5.5 Hz, 1H),1.27-1.23 (m, 3H).

Intermediate 165e-enantiomer 2:5-bromo-4′-((2-ethyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile

Peak 2 was collected and concentrated to give Intermediate165e-enantiomer 2 (100 mg, 0.23 mmol, 22% yield): enantiomeric excess95.4%. Chiral analytical RT=11.52 min. LC-MS (Method A5): 2.29 min,[M+H]⁺=438.1 and 440.1; ¹H NMR (500 MHz, CDCl₃) δ 7.69 (s, 1H), 7.64 (d,J=2.8 Hz, 2H), 7.56 (d, J=8.0 Hz, 2H), 7.33 (d, J=8.0 Hz, 2H), 4.78 (d,J=6.6 Hz, 2H), 4.28-4.11 (m, 2H), 4.02-3.98 (m, 1H), 3.97-3.87 (m, 1H),2.49-2.31 (m, 3H), 2.25-2.10 (m, 1H), 1.25-1.22 (m, 3H).

Intermediate 165f:4″42-ethyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)[1,1′:3′,1″-terphenyl]-4′-carbonitrile

A mixture of Intermediate 165d-enantiomer 1, 25 mg, 0.057 mmol) andphenylboronic acid (10.43 mg, 0.086 mmol) in THF (1 mL) was treated with1.5 M Na₂CO₃ (0.114 mL, 0.171 mmol) followed by PdCl₂(dppf) (4.66 mg,5.70 μmol). The resulting mixture was degassed with N₂ for 2 mM beforethe reaction vessel was sealed and irradiated in a microwave reactor at120° C. for 30 mM The cooled reaction mixture was concentrated todryness and the residue purified by ISCO (Hexanes/AcOEt, 0-100%) toafford the title compound (Intermediate 165f, 24 mg, 0.057 mmol, 100%yield) as an amber oil. LC-MS (Method A5): 2.48 min, [M+H]⁺=436.2; ¹HNMR (500 MHz, CDCl₃) δ 7.86 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.70 (br d,J=8.0 Hz, 1H), 7.64 (t, J=7.6 Hz, 4H), 7.55-7.49 (m, 2H), 7.49-7.43 (m,1H), 7.34 (d, J=8.0 Hz, 2H), 4.79 (d, J=6.3 Hz, 2H), 4.29-4.16 (m, 2H),4.11-3.98 (m, 1H), 3.97-3.86 (m, 1H), 2.68-2.35 (m, 3H), 2.20 (dt,J=12.4, 6.2 Hz, 1H), 1.27-1.23 (m, 3H).

Example 165-enantiomer 1:4″-((2-ethyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

To a solution of Intermediate 165f, 25 mg, 0.057 mmol) in toluene (1.5mL) was added dibutyltin oxide (28.4 mg, 0.114 mmol) and TMS-N₃ (0.076mL, 0.570 mmol). Then the reaction vessel was sealed and the mixture washeated at 100° C. overnight behind a blast shield (according to theprocedure described in J. Org. Chem, 1993, 58, 4139). After cooling, thereaction mixture was concentrated, re-solvated in DMF, filtered thenpurified via preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile PhaseB: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 11-51% B over 25 minutes,then a 5-minute hold at 100% B; Flow: 20 mL/min.) to afford 22.7 mg(0.047 mmol, 83% yield) of the title compound Example 165-enantiomer 1.LC-MS (Method A3): 1.29 min, [M+H]⁺=479.04; ¹H NMR (500 MHz, DMSO-d₆) δ7.87-7.79 (m, 3H), 7.75 (br d, J=10.1 Hz, 2H), 7.57-7.49 (m, 2H),7.47-7.40 (m, 1H), 7.39-7.38 (m, 1H), 7.20 (br d, J=7.9 Hz, 2H), 7.12(br d, J=7.9 Hz, 2H), 4.71 (s, 2H), 4.00 (br t, J=6.7 Hz, 2H), 3.81-3.69(m, 2H), 2.39 (q, J=7.3 Hz, 2H), 2.18 (dt, J=12.4, 7.7 Hz, 1H), 2.02(dt, J=12.2, 5.8 Hz, 1H), 1.08 (t, J=7.3 Hz, 3H).

The following examples have been similarly prepared from Intermediate165d-enantiomer 1 as described above for Example 165-enantiomer 1. Twoanalytical LC-MS injections were used to determine the final purity. Theretention time of one of them is reported for each compound and isreferred as Method A3, Method A4 or Method A5.

LC-MS m/z ¹H NMR [M + H]⁺; (500 MHz, DMSO-d₆) Ex Structure MW RT;(Method) δ ppm 166

492.58 493.3; 1.46 min (Method A3) 7.81-7.76 (m, 1H), 7.75-7.71 (m, 1H),7.69 (s, 1H), 7.61 (s, 1H), 7.57 (br d, J = 7.7 Hz, 1H), 7.38 (t, J =7.6 Hz, 1H), 7.25-7.18 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 4.70 (s, 2H),4.01 (dd, J = 7.4, 6.1 Hz, 2H), 3.80- 3.64 (m, 2H), 2.45-2.33 (m, 5H),2.19 (dt, J = 12.4, 7.7 Hz, 1H), 2.03 (dt, J = 12.2, 5.9 Hz, 1H), 1.09(t, J = 7.3 Hz, 3H) 167

494.56 495.38; 1.15 min (Method A3) 7.72-7.64 (m, 2H), 7.62 (s, 1H),7.40 (br d, J = 7.6 Hz, 1H), 7.21 (br t, J = 7.3 Hz, 1H), 7.18-7.13 (m,2H), 7.12-7.06 (m, 2H), 6.98 (br d, J = 7.6 Hz, 1H), 6.92 (br t, J = 7.2Hz, 1H), 4.69 (br s, 2H), 4.00 (br t, J = 6.6 Hz, 2H), 3.81-3.69 (m,2H), 2.43-2.31 (m, 2H), 2.24-2.11 (m, 1H), 2.06-1.99 (m, 1H), 1.07 (brt, J = 7.3 Hz, 3H)

The following examples have been similarly prepared from5-bromo-4′-((2-ethyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile(165e-enantiomer 2 as described above for Example 165-enantiomer 1. Twoanalytical LC-MS injections were used to determine the final purity. Theretention time of one of them is reported for each compound and isreferred as Method A3, Method A4 or Method A5.

LC-MS m/z ¹H NMR [M + H]⁺; (500 MHz, DMSO-d₆) Ex Structure MW RT;(Method) δ ppm 168

478.56 479.23; 1.33 min (Method A3) 7.84-7.76 (m, 3H), 7.75-7.72 (m,1H), 7.68 (s, 1H), 7.50 (t, J = 7.6 Hz, 2H), 7.45-7.36 (m, 1H), 7.21 (d,J = 8.1 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 4.70 (s, 2H), 4.01 (dd, J =7.5, 6.1 Hz, 2H), 3.80- 3.68 (m, 2H), 2.39 (q, J = 7.3 Hz, 2H), 2.18(dt, J = 12.3, 7.8 Hz, 1H), 2.09-1.96 (m, 1H), 1.09 (t, J = 7.3 Hz, 3H)169

492.58 493.02; 1.4 min (Method A3) 7.84-7.77 (m, 1H), 7.75-7.69 (m, 2H),7.63 (s, 1H), 7.59 (br d, J = 7.9 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H),7.24 (br d, J = 7.3 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H), 7.11 (br d, J =7.9 Hz, 2H), 4.70 (s, 2H), 4.00 (t, J = 6.7 Hz, 2H), 3.82-3.66 (m, 2H),2.46-2.32 (m, 5H), 2.18 (dt, J = 12.5, 7.8 Hz, 1H), 2.02 (dt, J = 12.1,5.9 Hz, 1H), 1.08 (t, J = 7.3 Hz, 3H) 170

494.56 495.25; 1.09 min (Method A3) 7.70-7.58 (m, 2H), 7.56 (s, 1H),7.42-7.31 (m, 1H), 7.23-7.12 (m, 3H), 7.07 (br d, J = 8.1 Hz, 2H), 6.97(d, J = 7.9 Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H), 4.68 (s, 2H), 4.00 (dd, J= 7.6, 6.0 Hz, 2H), 3.87- 3.61 (m, 2H), 2.39 (q, J = 7.3 Hz, 2H), 2.18(dt, J = 12.4, 7.8 Hz, 1H), 2.08-1.97 (m, 1H), 1.08 (t, J = 7.3 Hz, 3H)

Example 171:2-butyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-one

Intermediate 171a:4′-((2-butyl-4-oxo-8-oxa-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 155d (240 mg, 0.500 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (190 mg,0.749 mmol), KOAc (123 mg, 1.249 mmol) in dioxane (4 mL) was degassed bybubbling Ar for 1 min, then Pd (dppf)Cl₂ (20.40 mg, 0.025 mmol) wasadded. The mixture was sealed in a pressure vial and heated in an oilbath at 125° C. for 1 h. The reaction mixture was directly loaded onto asilica gel cartridge, purified by ISCO (DCM/MeOH, 0-20%) to afford thetitle compound (Intermediate 171a, 240 mg, 0.455 mmol, 91% yield). LC-MS(Method A5): 2.22 min, [M+H]⁺=446.1; ¹H NMR (500 MHz, CDCl₃) δ 7.92 (s,1H), 7.87 (dd, J=7.7, 0.8 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.58 (d,J=8.0 Hz, 2H), 7.32-7.26 (m, 2H), 4.77 (s, 2H), 4.09-4.03 (m, 2H),4.02-3.94 (m, 2H), 2.46-2.32 (m, 2H), 2.06 (ddd, J=13.5, 9.6, 4.4 Hz,2H), 1.65 (br t, J=7.7 Hz, 2H), 1.52 (br d, J=13.5 Hz, 2H), 1.42-1.38(m, 2H), 1.27 (s, 12H), 0.92 (t, J=7.3 Hz, 3H).

Intermediate 171b:4′-((2-butyl-4-oxo-8-oxa-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-5-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

A solution of Intermediate 171a (30 mg, 0.057 mmol),2-bromo-4-methylpyridine (24.46 mg, 0.142 mmol) and Pd-XPhos G3 (1.926mg, 2.275 μmol) in THF (1.5 mL) was added K₃PO₄ (1.0 M, 0.114 mL, 0.114mmol). The mixture was degassed with Ar for 1 min then sealed in apressure vial and heated at 120° C. in a microwave reactor for 45 min.The reaction mixture was concentrated and purified by ISCO (DCM/MeOH,0-20%) to afford the title compound (Intermediate 171b, 28 mg, 0.057mmol, 100% yield). LC-MS (Method A5): 2.18 min, [M+H]⁺=393.3; ¹H NMR(500 MHz, CDCl₃) δ 8.62-8.51 (m, 1H), 8.26-8.13 (m, 1H), 8.09-7.80 (m,1H), 7.67-7.60 (m, 2H), 7.52 (d, J=8.3 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H),7.26 (d, J=8.0 Hz, 1H), 7.17 (dd, J=8.3, 5.2 Hz, 1H), 6.95-6.84 (m, 1H),4.77 (d, J=12.7 Hz, 2H), 4.11-4.03 (m, 2H), 4.02-3.93 (m, 2H), 2.47 (d,J=8.0 Hz, 3H), 2.44-2.38 (m, 2H), 2.10-2.01 (m, 2H), 1.72-1.57 (m, 2H),1.53 (br d, J=13.2 Hz, 2H), 1.38 (br dd, J=14.6, 7.4 Hz, 2H), 0.93-0.83(m, 3H).

Example 171:2-butyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-one

To a solution of4′-((2-butyl-4-oxo-8-oxa-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)-5-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile(Intermediate 171b, 28.1 mg, 0.057 mmol) in toluene (1.5 mL) was addeddibutyltin oxide (28.4 mg, 0.114 mmol) and TMS-N₃ (0.076 mL, 0.570mmol). Then the reaction vessel was sealed and the mixture was heated at100° C. overnight behind a blast shield (according to the proceduredescribed in J. Org. Chem, 1993, 58, 4139). After cooling, the reactionmixture was concentrated, re-solvated in DMF, filtered then purified viapreparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂Owith 10 mM NH₄OAc; Gradient: 12-52% B over 20 minutes, then a 4-minutehold at 100% B; Flow: 20 mL/min) to afford 5.4 mg (9.68 μmol, 16.98%yield) of the title compound Example 171. LC-MS (Method A3): 1.36 min,[M+H]⁺=536.09; ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (br s, 2H), 8.35-7.71(m, 4H), 7.33-6.91 (m, 4H), 4.68 (br s, 2H), 3.99-3.81 (m, 2H),3.80-3.61 (m, 2H), 2.40 (br s, 3H), 2.34 (br d, J=7.9 Hz, 2H), 1.94-1.64(m, 2H), 1.60-1.40 (m, 2H), 1.37-1.23 (m, 4H), 0.91-0.77 (m, 3H).

Example 172:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-methyl-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-one

Intermediate 172a: N-(4-cyanotetrahydro-2H-pyran-4-yl)acetamide

To a solution of Intermediate 155a (500 mg, 3.07 mmol) in DCM (6 mL) wasadded potassium carbonate (2.2 g, 16 mmol) in H₂O (8 mL). The mixturewas cooled with an ice bath. Acetyl chloride (0.306 mL, 4.30 mmol) inDCM (4 mL) was added dropwise to the stirred solution. The reactionmixture was stirred at 0° C. for 2 h, and at rt for 3 h. The organicphase was collected. The aqueous phase was extracted (2×) with DCM. Thecombined organic phase was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by ISCO (DCM/AcOEt, 0-100%) togive the title compound (Intermediate 172a, 100 mg, 0.595 mmol, 19.34%yield) as oil. ¹H NMR (500 MHz, MeOH-d₄) δ 3.92 (dt, J=12.4, 4.1 Hz,2H), 3.78-3.62 (m, 2H), 2.33 (br d, J=13.5 Hz, 2H), 2.01 (s, 3H), 1.93(ddd, J=13.8, 10.0, 4.0 Hz, 2H).

Intermediate 172b: 2-methyl-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-onehydrochloride

To a solution of Intermediate 172a (100 mg, 0.595 mmol) in n-propanol(1.5 mL) was added 4N HCl in dioxane (1.486 mL, 5.95 mmol) dropwise. Themixture was heated up to 50° C. in oil bath for overnight. The mixturewas concentrated and dried under vacuum to give the title compound(Intermediate 172b, 120 mg, 0.586 mmol, 99% yield) as a whit solid. ¹HNMR (500 MHz, MeOH-d₄) δ 4.11-4.01 (m, 2H), 3.76 (ddd, J=12.3, 9.4, 3.0Hz, 2H), 2.61 (s, 3H), 2.11 (ddd, J=14.0, 9.6, 4.4 Hz, 2H), 1.93-1.80(m, 2H).

Intermediate 172c:(6′-(2-trityl-2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methylmethanesulfonate

A solution of I-003 (3 g, 5.26 mmol) and TEA (1.832 ml, 13.14 mmol) inTHF (10 mL) was cooled to 0° C. and treated with methanesulfonylchloride (0.498 ml, 6.31 mmol) dropwise. The mixture was slowly warmedto rt and stirred at rt for 1 h. The reaction was diluted with DCM,quenched with sat. NH₄Cl and extracted with DCM. The combined organicphase was washed with brine, dried over Na₂SO₄ and concentrated to thetitle compound (Intermediate 172c, 3.4 g, 5.24 mmol, 100% yield) as awhite solid. ¹H NMR (500 MHz, CDCl₃) δ 8.11 (d, J=8.0 Hz, 1H), 7.75 (dd,J=8.1, 1.8 Hz, 1H), 7.68 (d, J=7.4 Hz, 2H), 7.64 (d, J=1.7 Hz, 1H),7.53-7.47 (m, 2H), 7.44-7.35 (m, 4H), 7.33-7.30 (m, 4H), 7.29 (s, 3H),7.28-7.24 (m, 2H), 7.23-7.20 (m, 2H), 6.95 (d, J=7.7 Hz, 5H), 5.17 (s,2H), 2.87 (s, 3H).

Example 172:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-methyl-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-one

Intermediate 172b (23 mg, 0.112 mmol) was dissolved in DMF (1 mL). NaH(10.11 mg, 0.253 mmol) was added. The mixture was stirred at rt for 15min, Intermediate 172c (72.9 mg, 0.112 mmol) was added at 0° C. Thereaction mixture was stirred at rt for 1 h. The reaction mixture wasdiluted with EtOAc, washed with saturated NH₄C₁, brine, dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified byISCO (Hexanes/AcOEt, 0-100%) and concentrated. The sample wasre-dissolved in DCM (1 mL) and treated with 0.1 ml of 4N HCl in dioxanefor 1 h. The reaction mixture was concentrated, re-solvated in DMF,filtered then purified via preparative HPLC (Column: XBridge C18, 19×200mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc;Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 8-48% B over23 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to afford22.4 mg (0.047 mmol, 41.6% yield) of the title compound Example 172.LC-MS (Method A3): Retention Time: 1.26 min, [M+H]⁺=479.1; ¹H NMR (500MHz, DMSO-d₆) δ 7.79 (br d, J=7.8 Hz, 3H), 7.76-7.71 (m, 1H), 7.69 (s,1H), 7.50 (t, J=7.6 Hz, 2H), 7.45-7.36 (m, 1H), 7.21 (d, J=7.9 Hz, 2H),7.10 (d, J=8.0 Hz, 2H), 4.70 (s, 2H), 3.87 (dt, J=11.3, 3.8 Hz, 2H),3.80-3.67 (m, 2H), 2.09 (s, 3H), 1.86-1.74 (m, 2H), 1.34 (br d, J=13.5Hz, 2H).

Example 173:2-methyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-one

Intermediate 173a:5-bromo-4′-((2-methyl-4-oxo-8-oxa-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)biphenyl-2-carbonitrile

Intermediate 172b (100 mg, 0.489 mmol) was dissolved in DMF (3 mL). NaH(44.0 mg, 1.099 mmol) was added. The mixture was stirred at rt for 15min, I-002 (172 mg, 0.489 mmol) was added at 0° C. The reaction mixturewas stirred at rt for 1 h. The reaction mixture was diluted with EtOAc,washed with saturated NH₄Cl, brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by ISCO (Hexanes/AcOEt,0-100%) to give the title compound (Intermediate 173a, 120 mg, 0.274mmol, 56.0% yield) as a white solid. LC-MS (Method A5): 2.30 min,[M+H]⁺=438.1 and 440.1; ¹H NMR (500 MHz, CDCl₃) δ 7.67 (d, J=1.4 Hz,1H), 7.65-7.59 (m, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H),4.76 (s, 2H), 4.07-3.99 (m, 2H), 3.99-3.88 (m, 2H), 2.18 (s, 3H), 2.07(ddd, J=13.8, 9.9, 4.4 Hz, 2H), 1.48 (br d, J=13.5 Hz, 2H).

Example 173:2-methyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-8-oxa-1,3-diazaspiro[4.5]dec-1-en-4-onehas been similarly prepared from5-bromo-4′-((2-methyl-4-oxo-8-oxa-1,3-diazaspiro[4.5]dec-1-en-3-yl)methyl)biphenyl-2-carbonitrile(Intermediate 173a) as described above for

Example 171. LC-MS (Method A5): 1.06 min, [M+H]⁺=494.23; ¹H NMR (500MHz, DMSO-d₆) δ 8.55 (d, J=4.9 Hz, 1H), 8.22 (br d, J=8.5 Hz, 1H), 8.16(s, 1H), 7.99 (s, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.25 (br d, J=4.6 Hz,1H), 7.22-7.16 (m, 2H), 7.12 (br d, J=7.9 Hz, 2H), 4.71 (s, 2H),3.95-3.83 (m, 2H), 3.80-3.69 (m, 2H), 2.42 (s, 3H), 2.09 (s, 3H),1.87-1.76 (m, 2H), 1.33 (br d, J=13.1 Hz, 2H).

Example 174-enantiomer 1:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-methyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 174a: N-(3-cyanotetrahydrofuran-3-yl)acetamide

To a solution of Intermediate 158a (500 mg, 2.7 mmol) in DCM (10 mL) wasadded triethylamine (1.876 mL, 13.46 mmol). The mixture was cooled withan ice bath, acetyl chloride (0.335 mL, 4.71 mmol) in DCM (2 mL) wasadded dropwise to the stirred solution. The reaction mixture wasconcentrated and the residue was directly purified by ISCO (DCM/MeOH,0-20%) to give the title compound (Intermediate 174a, 300 mg, 1.946mmol, 72.0% yield) as oil. ¹H NMR (500 MHz, MeOH-d₄) δ 4.22 (d, J=9.6Hz, 1H), 4.05-3.91 (m, 3H), 2.61 (ddd, J=13.3, 7.8, 6.9 Hz, 1H), 2.43(ddd, J=13.4, 7.4, 5.9 Hz, 1H), 2.01 (s, 3H).

Intermediate 174b: 2-methyl-7-oxa-1,3-diazaspiro[4.4]non-1-en-4-onehydrochloride

To a solution of Intermediate 174a (300 mg, 1.946 mmol) in n-propanol (3mL) was added 4N HCl in dioxane (4.86 mL, 19.46 mmol) dropwise. Themixture was heated up to 50° C. in oil bath for overnight. The mixturewas concentrated and dried under vacuum to give the title compound(Intermediate 174b, 492 mg, 2.250 mmol, 100% yield) as a white solid.LC-MS (Method A5): 0.34 min, [M+H]⁺=155.1; ¹H NMR (500 MHz, MeOH-d₄) δ4.20-4.11 (m, 2H), 4.07-4.02 (m, 1H), 3.91 (d, J=9.9 Hz, 1H), 2.58 (s,2H), 2.57-2.49 (m, 1H), 2.40 (dt, J=13.7, 6.8 Hz, 1H).

Intermediate 174c:5-bromo-4′-((2-methyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile

Intermediate 174b (371 mg, 1.946 mmol) was dissolved in DMF (8 mL). NaH(175 mg, 4.38 mmol) was added. The mixture was stirred at rt for 15 min,I-002 (683 mg, 1.946 mmol) was added at 0° C. The reaction mixture wasstirred at rt for 1 h. The reaction mixture was diluted with EtOAc,washed with saturated NH₄Cl, brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by ISCO (DCM/AcOEt,0-100%) to give the title compound (Intermediate 174c, 560 mg, 1.320mmol, 67.8% yield) as a white solid. LC-MS (Method A5): 2.24 min,[M+H]⁺=424.1 and 426.1; ¹H NMR (500 MHz, CDCl₃) δ 7.69 (d, J=1.1 Hz,1H), 7.66-7.61 (m, 2H), 7.56 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.0 Hz, 2H),4.78 (d, J=6.3 Hz, 2H), 4.31-4.12 (m, 2H), 4.01 (d, J=8.8 Hz, 1H),3.95-3.82 (m, 1H), 2.41 (dt, J=12.4, 8.0 Hz, 1H), 2.27-2.10 (m, 4H).

Intermediate 174d-enantiomer 1:5-bromo-4′-((2-methyl-4-oxo-7-oxa-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)biphenyl-2-carbonitrile

Intermediate 174c-racemate (1.2 g, 2.83 mmol) were resolved into twopeaks on Instrument PIC Solution SFC Prep-200 with the followingpreparative chromatographic conditions: Column: Chiralpak AD-H, 30×250mm, 5 micron; Mobile Phase: 25% IPA/75% CO₂; Flow Conditions: 85 mL/min,120 Bar, 40° C.; Detector Wavelength: 238 nm; injection details: 1 mL of˜30 mg/mL in MeOH/ACN. Purity of each fraction was determined using theanalytical chromatographic condition below: Instrument: AuroraAnalytical SFC; Column: Chiralpak AD-H 4.6×250 mm, 5 micron; MobilePhase: 25% IPA/75% CO₂; Flow Conditions: 2.0 mL/min, 150 Bar, 40° C.;Detector Wavelength: 220 nm; Injection Details: 10 μL of 0.2 mg/mL inMeOH. Peak 1 was collected and concentrated to give Intermediate174d-enantiomer 1 (300 mg, 0.707 mmol, 25% yield): enantiomericexcess >99.0%. Chiral analytical RT=8.14 min LC-MS (Method A5): 2.24min, [M+H]⁺=424.1 and 426.1; ¹H NMR (500 MHz, CDCl₃) δ 7.70 (d, J=1.1Hz, 1H), 7.67-7.61 (m, 2H), 7.57 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.0 Hz,2H), 4.79 (d, J=6.3 Hz, 2H), 4.26-4.16 (m, 2H), 4.05-3.98 (m, 1H), 3.93(d, J=8.5 Hz, 1H), 2.57-2.29 (m, 1H), 2.25-2.11 (m, 4H)

Example 174-enantiomer 1 was prepared from Intermediate 174d-enantiomer1 as described above for Example 165. LC-MS (Method A3): 1.3 min,[M+H]⁺=465.25; ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (br d, J=7.9 Hz, 3H),7.76-7.72 (m, 1H), 7.70 (s, 1H), 7.55-7.47 (m, 2H), 7.45-7.36 (m, 1H),7.21 (d, J=7.9 Hz, 2H), 7.12 (br d, J=7.9 Hz, 2H), 4.71 (s, 2H),4.06-3.94 (m, 2H), 3.75 (q, J=8.9 Hz, 2H), 2.17 (dt, J=12.3, 7.9 Hz,1H), 2.08 (s, 3H), 2.02 (dt, J=11.7, 6.0 Hz, 1H).

Example 175: 2-ethyl-5,7-dimethyl-3-((6-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyridin-3-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 175a:4-chloro-2-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)benzonitrile

A mixture of Intermediate 039a (100 mg, 0.290 mmol) and(5-chloro-2-cyanophenyl)boronic acid (68.3 mg, 0.377 mmol) in THF (3 mL)was treated with 1.5 M Na₂CO₃ (0.579 mL, 0.869 mmol) followed byPdCl₂(dppf) (11.83 mg, 0.014 mmol). The resulting mixture was degassedwith N₂ for 2 min before the reaction vessel was sealed and irradiatedin a microwave reactor at 125° C. for 70 min. The cooled reactionmixture was diluted with DCM and extracted. The combined organic layerwas washed with brine, dried over MgSO₄, and concentrated. The crudesample in 2 ml of DCM was treated with TEA (0.202 mL, 1.448 mmol)followed by TFAA (0.061 mL, 0.434 mmol). The mixture was stirred at RTfor 1 hour, then concentrated to dryness and the residue purified byISCO (Hexanes/AcOEt, 0-100%) to afford the title compound (Intermediate175a, 65 mg, 0.162 mmol, 55.8% yield) as an amber oil. LC-MS (MethodA5): 2.18 min, [M+H]⁺=402.1; ¹H NMR (500 MHz, CDCl₃) δ 8.73 (d, J=1.7Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.74 (dd, J=9.9, 8.5 Hz, 2H), 7.63 (dd,J=8.3, 2.2 Hz, 1H), 7.50 (dd, J=8.4, 2.1 Hz, 1H), 6.94 (s, 1H), 5.56 (s,2H), 2.88 (q, J=7.7 Hz, 2H), 2.66 (s, 3H), 2.62 (s, 3H), 1.40 (t, J=7.6Hz, 3H).

Intermediate 175b:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-3′-methylbiphenyl-4-carbonitrile

A mixture of Intermediate 175a (32 mg, 0.080 mmol) and m-tolylboronicacid (32.5 mg, 0.239 mmol) in THF (1 mL) was treated with 1.0 Mphosphoric acid, potassium salt (0.143 mL, 0.143 mmol) followed byPd-XPhos G3 (6.74 mg, 7.96 mol). The resulting mixture was degassed withN₂ for 2 min before the reaction vessel was sealed and irradiated in amicrowave reactor at 140° C. for 45 min. The cooled reaction mixture wasconcentrated to dryness and the residue purified by ISCO (Hexanes/AcOEt,0-100%) to afford the title compound (Intermediate 175b, 36 mg, 0.079mmol, 99% yield) as an amber oil. LC-MS (Method A5): 2.44 min,[M+H]⁺=458.2; ¹H NMR (500 MHz, CDCl₃) δ 8.75 (d, J=1.4 Hz, 1H), 8.04 (d,J=1.7 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.73 (dd,J=8.3, 1.7 Hz, 1H), 7.65 (dd, J=8.0, 2.2 Hz, 1H), 7.49-7.42 (m, 2H),7.38 (t, J=7.6 Hz, 1H), 7.26 (d, J=7.4 Hz, 1H), 6.94 (s, 1H), 5.57 (s,2H), 2.90 (q, J=7.6 Hz, 2H), 2.66 (s, 3H), 2.63 (s, 3H), 2.45 (s, 3H),1.41 (t, J=7.6 Hz, 3H).

Example 175:3-((6′-(2H-tetrazol-5-yl)-2″-(trifluoromethoxy)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-3′-methyl-[1,1′-biphenyl]-4-carbonitrile(Intermediate 175b, 36 mg, 0.079 mmol) in toluene (1.5 mL) was addeddibutyltin oxide (39.2 mg, 0.157 mmol) and TMS-N₃ (0.104 mL, 0.787mmol). Then the reaction vessel was sealed and the mixture was heated at100° C. overnight behind a blast shield (according to the proceduredescribed in J. Org. Chem, 1993, 58, 4139). After cooling, the reactionmixture was concentrated, re-solvated in DMF, filtered then purified viapreparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂Owith 10 mM NH₄OAc; Gradient: 15-55% B over 20 minutes, then a 4-minutehold at 100% B; Flow: 20 mL/min to afford 29.6 mg (0.057 mmol, 72%yield) of the title compound Example 175. LC-MS (Method A3): 1.47 min,[M+H]⁺=501.23; ¹H NMR (500 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.95 (s, 1H),7.91 (br d, J=8.2 Hz, 1H), 7.78 (d, J=7.9 Hz, 1H), 7.64 (s, 1H), 7.61(br d, J=7.9 Hz, 1H), 7.56-7.54 (m, 1H), 7.53-7.48 (m, 1H), 7.40 (t,J=7.5 Hz, 1H), 7.26 (br d, J=7.3 Hz, 1H), 6.98 (s, 1H), 5.52 (s, 2H),2.85 (q, J=7.6 Hz, 2H), 2.56 (s, 6H), 2.40 (s, 3H), 1.27 (t, J=7.5 Hz,3H).

Example 176:3-((6-(4-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Example 176 has been similarly prepared from Intermediate 175a asdescribed above for Example 001. LC-MS (Method A3): 1.37 min,[M+H]⁺=487.22; ¹H NMR (500 MHz, DMSO-d₆) δ 8.36 (s, 1H), 7.94 (s, 1H),7.90 (br d, J=8.0 Hz, 1H), 7.83-7.73 (m, 3H), 7.51 (br t, J=7.4 Hz, 3H),7.44 (br d, J=4.7 Hz, 2H), 6.97 (s, 1H), 5.51 (s, 2H), 2.84 (q, J=7.3Hz, 2H), 2.55 (s, 6H), 1.26 (t, J=7.4 Hz, 3H).

Example 177:2-ethyl-5,7-dimethyl-3-((5-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyridin-2-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 177a: (5-bromopyridin-2-yl)methyl methanesulfonate

A solution of (5-bromopyridin-2-yl)methanol (500 mg, 2.66 mmol) in THF(10 mL) was cooled to 0° C. and treated with TEA (0.482 mL, 3.46 mmol)and methanesulfonyl chloride (0.252 mL, 3.19 mmol). The mixture wasslowly warmed to RT and stirred for 1 hour. The reaction was dilutedwith DCM, quenched with a saturated aqueous solution of NH₄Cl and themixture was extracted with DCM. The combined organic layer was washedwith brine, dried over MgSO₄, and concentrated to(5-bromopyridin-2-yl)methyl methanesulfonate (Intermediate 177a, 700 mg,2.63 mmol, 99% yield) which was used for next step without purification.LC-MS (Method A5): 1.72 min, [M+H]⁺=265.9 and 267.9; ¹H NMR (500 MHz,CDCl₃) δ 8.68 (d, J=2.2 Hz, 1H), 7.90 (dd, J=8.3, 2.2 Hz, 1H), 7.39 (d,J=8.3 Hz, 1H), 5.29 (s, 2H), 3.10 (s, 3H).

Intermediate 177b:3-((5-bromopyridin-2-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001c (200 mg, 1.141 mmol) in DMF (4.1 mL)was added sodium hydride (59.3 mg, 1.484 mmol) at RT and the reactionwas stirred vigorously for 30 min. Then a solution of Intermediate 177a(349 mg, 1.313 mmol) in DMF (1.6 mL) was added and the resultingreaction mixture was allowed to stir for 2 h before being quenched witha saturated aqueous solution of NH₄Cl. The mixture was diluted withEtOAc and extracted. The organic phase was dried over MgSO₄, filteredand concentrated before being purified by ISCO (Hex/EtOAc, 0-100%) toafford the title compound (Intermediate 177b, 320 mg, 0.927 mmol, 81%yield) as a white solid. LC-MS (Method A5): 2.02 min, [M+H]⁺=345.1 and347.1; ¹H NMR (500 MHz, CDCl₃) δ 8.62 (d, J=2.2 Hz, 1H), 7.69 (dd,J=8.3, 2.2 Hz, 1H), 7.07-6.69 (m, 2H), 5.52 (s, 2H), 2.87 (q, J=7.4 Hz,2H), 2.64 (s, 3H), 2.58 (s, 3H), 1.34 (t, J=7.6 Hz, 3H).

Intermediate 177c:6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-3-ylboronicacid

A solution of Intermediate 177b (320 mg, 0.927 mmol), KOAc (182 mg,1.854 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(259 mg, 1.020 mmol) and PdCl₂(dppf) (37.8 mg, 0.046 mmol) in dioxane (5mL) was degassed with N₂ for 2 min before the reaction vessel was sealedand heated at 100° C. for overnight. The mixture was cooled and filteredthrough celite and purified via preparative HPLC (Column Phenomenex AXIALuna 100×30 mm 5 u s; Mobile Phase A: 10:90 ACN: H₂O with 10 mM TFA;Mobile Phase B: 90:10 ACN: H₂O with 10 mM TFA; Gradient: 0-100% B over10 minutes, then a 2-minute hold at 100% B; Flow: 40 mL/min.) to afford400 mg (0.92 mmol, 98% yield) of the title compound (Intermediate 177c)as TFA salt. LC-MS (Method A5): 1.58 min, [M+H]⁺=311.2; ¹H NMR (500 MHz,MeOH-d4) δ 8.64 (br d, J=10.7 Hz, 1H), 8.24-8.03 (m, 1H), 7.58 (br t,J=7.0 Hz, 1H), 7.34 (s, 1H), 5.89 (br d, J=5.5 Hz, 2H), 4.92 (br s, 2H),2.67 (s, 3H), 2.60 (s, 3H), 1.46 (t, J=7.6 Hz, 3H).

Intermediate 177d:4-chloro-2-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-3-yl)benzonitrile

A mixture of Intermediate 177c (177 mg, 0.418 mmol) and4-chloro-2-iodobenzonitrile (100 mg, 0.380 mmol) in THF (5 mL) wastreated with 1.5 M Na₂CO₃ (1.012 mL, 1.518 mmol) followed by PdCl₂(dppf)(15.50 mg, 0.019 mmol). The resulting mixture was degassed with N₂ for 2mM before the reaction vessel was sealed and irradiated in a microwavereactor at 100° C. for 30 min. The cooled reaction mixture was dilutedwith DCM and extracted. The combined organic layer was washed withbrine, dried over MgSO₄, and concentrated to dryness and the residuepurified by ISCO (Hexanes/AcOEt, 0-100%) to afford the title compound(Intermediate 177d, 120 mg, 0.299 mmol, 79% yield) as a yellow oil.LC-MS (Method A5): 2.17 min, [M+H]⁺=402.1; ¹H NMR (500 MHz, CDCl₃) δ8.72 (d, J=2.2 Hz, 1H), 7.80 (dd, J=8.1, 2.3 Hz, 1H), 7.74 (d, J=8.8 Hz,1H), 7.54-7.43 (m, 2H), 7.13 (d, J=8.3 Hz, 1H), 6.92 (s, 1H), 5.66 (s,2H), 2.92 (q, J=7.4 Hz, 2H), 2.66 (s, 3H), 2.61 (s, 3H), 1.37 (t, J=7.6Hz, 3H).

Intermediate 177e:3-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-3-yl)-3′-methylbiphenyl-4-carbonitrile

A mixture of Intermediate 177d (33 mg, 0.082 mmol) and m-tolylboronicacid (33.5 mg, 0.246 mmol) in THF (1 mL) was treated with 1.0 Mphosphoric acid, potassium salt (0.148 mL, 0.148 mmol) followed byPd-XPhos G3 (6.95 mg, 8.21 μmol). The resulting mixture was degassedwith N₂ for 2 min before the reaction vessel was sealed and irradiatedin a microwave reactor at 140° C. for 45 min. The cooled reactionmixture was concentrated to dryness and the residue purified by ISCO(Hexanes/AcOEt, 0-100%) to afford the title compound (Intermediate 177e,26 mg, 0.057 mmol, 69.2% yield) as an amber oil. LC-MS (Method A5): 2.44min, [M+H]⁺=458.2; ¹H NMR (500 MHz, CDCl₃) δ 8.80 (d, J=1.7 Hz, 1H),7.90-7.85 (m, 2H), 7.72 (dd, J=8.3, 1.7 Hz, 1H), 7.69 (d, J=1.4 Hz, 1H),7.47-7.37 (m, 4H), 7.15 (d, J=8.3 Hz, 1H), 6.93 (s, 1H), 5.68 (s, 2H),2.95 (q, J=7.4 Hz, 2H), 2.67 (s, 3H), 2.62 (s, 3H), 2.46 (s, 3H), 1.39(t, J=7.6 Hz, 3H).

Example 177:2-ethyl-5,7-dimethyl-3-((5-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyridin-2-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 177e (26 mg, 0.057 mmol) in toluene (1.5mL) was added dibutyltin oxide (28.3 mg, 0.114 mmol) and TMS-N₃ (0.075mL, 0.568 mmol). Then the reaction vessel was sealed and the mixture washeated at 100° C. overnight behind a blast shield (according to theprocedure described in J. Org. Chem, 1993, 58, 4139). After cooling, thereaction mixture was concentrated, re-solvated in DMF, filtered thenpurified via preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile PhaseB: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 19-59% B over 19 minutes,then a 5-minute hold at 100% B; Flow: 20 mL/min) to afford 12.5 mg(0.025 mmol, 43.6% yield) of the title compound Example 177. LC-MS(Method A3): 1.54 min, [M+H]⁺=501.07; ¹H NMR (500 MHz, DMSO-d₆) δ 8.32(d, J=1.5 Hz, 1H), 7.84-7.73 (m, 2H), 7.63 (br d, J=15.9 Hz, 2H),7.60-7.53 (m, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.21 (br d, J=7.3 Hz, 1H),7.06 (d, J=7.9 Hz, 1H), 6.94 (s, 1H), 5.55 (s, 2H), 2.85 (q, J=7.3 Hz,2H), 2.55 (s, 3H), 2.50 (s, 3H), 2.38 (s, 3H), 1.29 (t, J=7.5 Hz, 3H).

The following examples have been similarly prepared from Intermediate177d as described above for Example 177. Two analytical LC-MS injectionswere used to determine the final purity. The retention time of one ofthem is reported for each compound and is referred as Method A3, MethodA4 or Method A5.

LC-MS m/z [M + H]⁺; RT; ¹H NMR (500 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 178

502.58 503.28; 1.27 min (Method A3) 8.28 (s, 1H), 7.76 (s, 2H), 7.62 (s,1H), 7.57 (hr d, J = 7.9 Hz, 1H), 7.41 (hr d, J = 7.3 Hz, 1H), 7.22 (brt, J = 7.6 Hz, 1H), 7.09 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 7.9 Hz, 1H),6.96-6.89 (m, 2H), 5.56 (s, 2H), 2.83 (q, J = 7.5 Hz, 2H), 2.57 (s, 3H),2.50 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H) 179

486.58 487.31; 1.58 min (Method A3) 8.33 (d, J = 1.5 Hz, 1H), 7.93 (brd, J = 8.2 Hz, 1H), 7.86-7.74 (m, 4H), 7.61 (dd, J = 7.9, 2.1 Hz, 1H),7.55-7.47 (m, 2H), 7.47-7.36 (m, 1H), 7.17 (d, J = 8.2 Hz, 1H), 6.96 (s,1H), 5.58 (s, 2H), 2.83 (q, J = 7.6 Hz, 2H), 2.56 (s, 3H), 2.49 (s, 3H),1.26 (t, J = 7.5 Hz, 3H) 180

516.61 517.2; 1.11 min (Method A3) 8.34 (s, 1H), 7.95 (br d, J = 8.2 Hz,1H), 7.89-7.77 (m, 4H), 7.64 (dd, J = 8.2, 1.8 Hz, 1H), 7.46 (br d, J =7.9 Hz, 2H), 7.27 (s, 1H), 7.07 (s, 1H), 5.67 (s, 2H), 4.58 (s, 2H),2.93 (q, J = 7.5 Hz, 2H), 2.57 (s, 2H), 2.56 (br s, 3H), 1.30 (t, J =7.5 Hz, 3H)

Example 181:4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3,5-dimethyl-[1,1′:3′,1″-terphenyl]-4′-carboxylicacid

Intermediate 181a: methyl5-chloro-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)biphenyl-2-carboxylate

A mixture of Intermediate 001d (100 mg, 0.256 mmol), and methyl4-chloro-2-iodobenzoate (68.9 mg, 0.232 mmol) in THF (5 mL) was treatedwith 1.5 M Na₂CO₃ (0.465 mL, 0.697 mmol) followed by PdCl₂(dppf) (9.49mg, 0.012 mmol). The resulting mixture was degassed with N₂ for 2 minbefore the reaction vessel was sealed and irradiated in a microwavereactor at 100° C. for 30 min. The cooled reaction mixture was dilutedwith DCM and extracted. The combined organic layer was washed withbrine, dried over MgSO₄, and concentrated to dryness and the residuepurified by ISCO (Hexanes/AcOEt, 0-100%) to afford the title compound(Intermediate 181a, 100 mg, 0.230 mmol, 99% yield) as a yellow oil.LC-MS (Method A5): 2.30 min, +=434.1; ¹H NMR (500 MHz, CDCl₃) δ 7.80 (d,J=8.3 Hz, 1H), 7.40 (dd, J=8.4, 2.1 Hz, 1H), 7.33 (d, J=1.9 Hz, 1H),7.25-7.20 (m, 2H), 7.19-7.14 (m, 2H), 6.93 (s, 1H), 5.53 (s, 2H), 3.63(s, 3H), 2.84 (q, J=7.5 Hz, 2H), 2.67 (s, 3H), 2.63 (s, 3H), 1.35 (t,J=7.6 Hz, 3H).

Example 181:4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3,5-dimethyl-[1,1′:3′,1″-terphenyl]-4′-carboxylicacid

A mixture of Intermediate 181^(a) (20 mg, 0.046 mmol) and(3,5-dimethylphenyl)boronic acid (20.74 mg, 0.138 mmol) in THF (1 mL)was treated with 1.0 M phosphoric acid, potassium salt (0.083 mL, 0.083mmol) followed by Pd-XPhos G3 (1.951 mg, 2.304 mol). The resultingmixture was degassed with N₂ for 2 min before the reaction vessel wassealed and irradiated in a microwave reactor at 140° C. for 45 min. Thecooled reaction mixture was treated with MeOH (0.5 mL) and 2.0 M NaOH(0.138 mL, 0.277 mmol). The mixture was reheated in a microwave reactorat 100° C. for 15 min. After cooling, the reaction mixture wasconcentrated, re-solvated in DMF, filtered then purified via preparativeHPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A:5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10mM NH₄OAc; Gradient: 28-68% B over 20 minutes, then a 4-minute hold at100% B; Flow: 20 mL/min.) to afford 8.5 mg (0.017 mmol, 37.7% yield) ofthe title compound Example 181. LC-MS (Method A3): 1.81 min,[M+H]⁺=490.34. ¹H NMR (500 MHz, DMSO-d₆) δ 7.80 (br d, J=8.0 Hz, 1H),7.69 (br d, J=8.0 Hz, 1H), 7.53 (s, 1H), 7.36 (br d, J=8.0 Hz, 2H), 7.33(s, 1H), 7.34-7.31 (m, 1H), 7.19 (br d, J=7.9 Hz, 2H), 7.03 (s, 1H),6.96 (s, 1H), 5.51 (s, 2H), 2.83 (q, J=7.5 Hz, 2H), 2.54 (s, 6H), 2.33(s, 6H), 1.29 (t, J=7.4 Hz, 3H).

The following examples have been similarly prepared from Intermediate181a as described above for Example 181. Two analytical LC-MS injectionswere used to determine the final purity. The retention time of one ofthem is reported for each compound and is referred as Method A3, MethodA4 or Method A5.

LC-MS m/z [M + H]⁺; RT; ¹H NMR (500 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 182

475.59 476.13; 1.67 min (Method A3) 7.76 (br d, J = 7.9 Hz, 1H), 7.69(br d, J = 7.6 Hz, 1H), 7.65-7.47 (m, 5H), 7.39-7.31 (m, 2H), 7.20 (brd, J = 7.0 Hz, 1H), 7.15 (br d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 5.50 (s,2H), 2.81 (q, J = 7.5 Hz, 2H), 2.55 (s, 3H), 2.51 (s, 3H), 2.35 (s, 3H),1.28- 1.23 (m, 3H). 183

491.59 492.29; 1.16 min (Method A3) 7.83 (d, J = 7.9 Hz, 1H), 7.74 (brd, J = 8.2 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.57 (s, 1H), 7.42 (br d,J = 7.9 Hz, 2H), 7.39 (br d, J = 7.9 Hz, 2H), 7.25 (br d, J = 7.6 Hz,2H), 7.16- 7.10 (m, 1H), 5.61 (s, 2H), 4.55 (s, 2H), 2.97 (q, J = 7.6Hz, 2H), 2.57 (s, 3H), 2.56 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H) 184

477.56 478.32; 1.27 min (Method A3) 7.74 (br d, J = 7.9 Hz, 1H), 7.60(br d, J = 7.6 Hz, 1H), 7.46 (s, 1H), 7.35-7.26 (m, 3H), 7.18 (br t, J =7.5 Hz, 1H), 7.14 (br d, J = 7.6 Hz, 2H), 6.98-6.90 (m, 2H), 6.88 (br t,J = 7.2 Hz, 1H), 5.49 (s, 2H), 2.80 (q, J = 7.3 Hz, 2H), 2.54 (s, 6H),1.23 (br d, J = 7.6 Hz, 3H). 185

532.64 533.24; 1.34 min (Method A3) 7.86-7.80 (m, 2H), 7.78 (br d, J =7.9 Hz, 2H), 7.63 (s, 1H), 7.58- 7.46 (m, 2H), 7.39 (br d, J = 7.9 Hz,2H), 7.18 (br d, J = 8.2 Hz, 2H), 6.98 (s, 1H), 5.53 (s, 2H), 3.03- 2.93(m, 6H), 2.84 (q, J = 7.4 Hz, 2H), 2.56 (s, 3H), 2.54 (s, 3H), 1.28 (t,J = 7.5 Hz, 3H)

Example 186:2-ethyl-5,7-dimethyl-3-((5-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyrazin-2-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 186a: 2-bromo-5-(bromomethyl)pyrazine

2-bromo-5-methylpyrazine (300 mg, 1.734 mmol) was dissolved in carbontetrachloride (8 mL), NBS (370 mg, 2.081 mmol) and benzoyl peroxide(21.00 mg, 0.087 mmol) were added, and the resulting mixture was heatedand refluxed for overnight. The reaction solution was returned to RT,concentrated under reduced pressure and purified by ISCO (Hexanes/AcOEt,0-100%) to afford the title compound (Intermediate 186a, 140 mg, 0.556mmol, 32.1% yield) as a white solid. LC-MS (Method A5): 1.77 min,[M+H]⁺=250.9 and 251.9; ¹H NMR (500 MHz, CDCl₃) δ 8.80 (s, 2H), 4.58 (s,2H).

Intermediate 186b:3-((5-bromopyrazin-2-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001c (108 mg, 0.618 mmol) in DMF (2.0 mL)was added sodium hydride (29.6 mg, 0.741 mmol) at RT and the reactionwas stirred vigorously for 30 min. Then a solution of Intermediate 186a(140 mg, 0.648 mmol) in DMF (0.8 mL) was added and the resultingreaction mixture was allowed to stir for 2 h before being quenched witha saturated aqueous solution of NH₄Cl. The mixture was diluted withEtOAc and extracted. The organic phase was dried over MgSO₄, filteredand concentrated before being purified by ISCO (Hex/EtOAc, 0-100%) toafford the title compound (Intermediate 186b, 140 mg, 0.404 mmol, 65.5%yield) as a white solid. LC-MS (Method A5): 1.90 min, [M+H]⁺=346.0 and348.0; ¹H NMR (500 MHz, CDCl₃) δ 8.60 (d, J=1.1 Hz, 1H), 8.36 (s, 1H),6.89 (s, 1H), 5.53 (s, 2H), 2.96 (q, J=7.7 Hz, 3H), 2.62 (s, 3H), 2.57(s, 3H), 1.40 (t, J=7.6 Hz, 3H).

Intermediate 186c:4-chloro-2-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)benzonitrile

A mixture of Intermediate 186b (100 mg, 0.289 mmol) and(5-chloro-2-cyanophenyl)boronic acid (68.1 mg, 0.375 mmol) in THF (3 mL)was treated with 1.5 M Na₂CO₃ (0.578 mL, 0.866 mmol) followed byPdCl₂(dppf) (11.79 mg, 0.014 mmol). The resulting mixture was degassedwith N₂ for 2 min before the reaction vessel was sealed and irradiatedin a microwave reactor at 125° C. for 1 hour. The cooled reactionmixture was diluted with DCM and extracted. The combined organic layerwas washed with brine, dried over MgSO₄, and concentrated. The crudesample in 2 ml of DCM was treated with TEA (0.201 mL, 1.444 mmol)followed by TFAA (0.061 mL, 0.433 mmol). The mixture was stirred at RTfor 1 hour, then concentrated to dryness and the residue purified byISCO (Hexanes/AcOEt, 0-100%) to afford the title compound (Intermediate186c, 80 mg, 0.199 mmol, 68.8% yield) as an amber oil. LC-MS (MethodA5): 2.16 min, [M+H]⁺=403.1; ¹H NMR (500 MHz, CDCl₃) δ 9.00 (d, J=1.4Hz, 1H), 8.70 (d, J=0.8 Hz, 1H), 7.84 (d, J=1.9 Hz, 1H), 7.78 (d, J=8.3Hz, 1H), 7.56 (dd, J=8.3, 1.9 Hz, 1H), 6.92 (s, 1H), 5.68 (s, 2H), 3.00(q, J=7.4 Hz, 2H), 2.65 (s, 3H), 2.60 (s, 3H), 1.43 (t, J=7.6 Hz, 3H).

Intermediate 186d:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)-3′-methylbiphenyl-4-carbonitrile

A mixture of Intermediate 186c (40 mg, 0.099 mmol) and tolylboronic acid(40.5 mg, 0.298 mmol) in THF (1 mL) was treated with 1.0 M phosphoricacid, potassium salt (0.179 mL, 0.179 mmol) followed by Pd-XPhos G3(8.40 mg, 9.93 mol). The resulting mixture was degassed with N₂ for 2min before the reaction vessel was sealed and irradiated in a microwavereactor at 140° C. for 60 min. The cooled reaction mixture wasconcentrated to dryness and the residue purified by ISCO (Hexanes/AcOEt,0-100%) to afford the title compound (Intermediate 186d, 45 mg, 0.098mmol, 99% yield) as a colorless oil. LC-MS (Method A5): 2.37 min,[M+H]⁺=459.2; ¹H NMR (500 MHz, CDCl₃) δ 9.02 (d, J=1.1 Hz, 1H), 8.71 (s,1H), 7.99 (d, J=1.4 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.77 (dd, J=8.0,1.7 Hz, 1H), 7.46-7.41 (m, 2H), 7.40-7.33 (m, 1H), 7.30-7.23 (m, 1H),6.91 (s, 1H), 5.68 (s, 2H), 3.01 (q, J=7.4 Hz, 2H), 2.64 (s, 3H), 2.60(s, 3H), 2.44 (s, 3H), 1.42 (t, J=7.6 Hz, 3H)

Example 186:2-ethyl-5,7-dimethyl-3-((5-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyrazin-2-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 186d (35 mg, 0.076 mmol) in toluene (1.5mL) was added dibutyltin oxide (38.0 mg, 0.153 mmol) and TMS-N₃ (0.101mL, 0.763 mmol). Then the reaction vessel was sealed and the mixture washeated at 100° C. overnight behind a blast shield (according to theprocedure described in J. Org. Chem, 1993, 58, 4139). After cooling, thereaction mixture was concentrated, re-solvated in DMF, filtered thenpurified via preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 ACN: H₂O with 0.1% trifluoroacetic acid; Gradient:20-60% B over 19 minutes, then a 5-minute hold at 100% B; Flow: 20mL/min) to afford 23.1 mg (0.046 mmol, 60.3% yield) of the titlecompound Example 186. LC-MS (Method A3): 1.49 min, [M+H]⁺=502.25; ¹H NMR(500 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.28 (br s, 1H), 7.92 (br d, J=7.9Hz, 1H), 7.87-7.78 (m, 2H), 7.59 (br s, 1H), 7.56 (br d, J=7.6 Hz, 1H),7.37 (br t, J=7.5 Hz, 1H), 7.21 (br d, J=7.3 Hz, 1H), 6.94 (s, 1H), 5.64(s, 2H), 2.95-2.90 (m, 2H), 2.75 (s, 2H), 2.56 (s, 3H), 2.52 (br s, 3H),2.39 (s, 3H), 1.31 (br t, J=7.3 Hz, 3H).

Example 187:3-((5-(4-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)pyrazin-2-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Example 187 has been similarly prepared from Intermediate 186c asdescribed above for Example 186. LC-MS (Method A3): 1.32 min,[M+H+H]⁺=488.22; ¹H NMR (500 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.65 (s, 1H),8.06 (s, 1H), 8.02 (br d, J=8.2 Hz, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.86(br d, J=7.6 Hz, 2H), 7.56-7.50 (m, 2H), 7.48-7.43 (m, 1H), 7.12 (s,1H), 5.80 (s, 2H), 3.12-2.96 (m, 2H), 2.56 (s, 6H), 1.40-1.32 (m, 3H).

Example 188:2-ethyl-5,7-dimethyl-3-((5-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyrimidin-2-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 188a: 5-bromo-2-(bromomethyl)pyrimidine

5-bromo-2-methylpyrimidine (1.0 g, 5.78 mmol) was dissolved in carbontetrachloride (15 mL), NBS (1.234 g, 6.94 mmol) and benzoyl peroxide(0.070 g, 0.289 mmol) were added, and the resulting mixture was heatedand refluxed for overnight. The reaction solution was returned to RT,concentrated under reduced pressure and purified by ISCO (Hexanes/AcOEt,0-100%) to afford the title compound (Intermediate 188a, 370 mg, 1.469mmol, 25.4% yield) as a white solid. LC-MS (Method A5): 1.77 min,[M+H]⁺=252.8; ¹H NMR (500 MHz, CDCl₃) δ 8.82 (s, 2H), 4.60 (s, 2H).

Intermediate 188b:3-((5-bromopyrimidin-2-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001c (370 mg, 2.111 mmol) in DMF (7.5 mL)was added sodium hydride (110 mg, 2.74 mmol) at RT and the reaction wasstirred vigorously for 30 min. Then a solution of Intermediate 188a (558mg, 2.217 mmol) in DMF (3.0 mL) was added and the resulting reactionmixture was allowed to stir for 2 h before being quenched with asaturated aqueous solution of NH₄Cl. The mixture was diluted with EtOAcand extracted. The organic phase was dried over MgSO₄, filtered andconcentrated before being purified by ISCO (Hex/EtOAc, 0-100%) to affordthe title compound (Intermediate 188b, 320 mg, 0.924 mmol, 43.8% yield)as a white solid. LC-MS (Method A5): 1.80 min, [M+H]⁺=346.1 and 348.1;¹H NMR (500 MHz, CDCl₃) δ 8.72 (s, 2H), 6.89 (s, 1H), 5.66 (s, 2H), 2.83(q, J=7.7 Hz, 2H), 2.66 (s, 3H), 2.56 (s, 3H), 1.37 (t, J=7.6 Hz, 3H).

Intermediate 188c:2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-5-ylboronicacid

Intermediate 188b (320 mg, 0.924 mmol), KOAc (181 mg, 1.848 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (258 mg,1.017 mmol) and PdCl₂(dppf) (37.7 mg, 0.046 mmol) in dioxane (5.0 mL)was degassed with N₂ for 2 min before the reaction vessel was sealed andheated at 100° C. for overnight. The mixture was cooled and filteredthrough CELITE and purified via preparative HPLC (Column: PhenomenexAXIA Luna 100×30 mm 5 u s; Mobile Phase A: 10:90 ACN: H₂O with 10 mMTFA; Mobile Phase B: 90:10 ACN: H₂O with 10 mM TFA; Gradient: 0-100% Bover 10 minutes, then a 2-minute hold at 100% B; Flow: 40 mL/min.) toafford 390 mg (0.917 mmol, 99% yield) of the title compound(Intermediate 188c) as TFA salt. LC-MS (Method A5): 1.60 min,[M+H]⁺=312.2; ¹H NMR (400 MHz, CDCl₃) δ 8.94 (s, 2H), 7.16 (s, 1H), 5.95(s, 2H), 3.17 (q, J=7.6 Hz, 2H), 2.66 (s, 3H), 2.58 (s, 3H), 1.52-1.40(m, 3H).

Intermediate 188d:4-chloro-2-(2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-5-yl)benzonitrile

A mixture of Intermediate 188c (200 mg, 0.470 mmol) and4-chloro-2-iodobenzonitrile 124 mg, 0.470 mmol) in THF (8 mL) wastreated with 1.5 M Na₂CO₃ (1.254 mL, 1.882 mmol)) followed byPdCl₂(dppf) (19.21 mg, 0.024 mmol). The resulting mixture was degassedwith N₂ for 2 min before the reaction vessel was sealed and irradiatedin a microwave reactor at 100° C. for 30 min. The cooled reactionmixture was diluted with DCM and extracted. The combined organic layerwas washed with brine, dried over MgSO₄, and concentrated to dryness andthe residue purified by ISCO (Hexanes/AcOEt, 0-100%) to afford the titlecompound (Intermediate 188d, 100 mg, 0.248 mmol, 52.8% yield) as anoff-white solid. LC-MS (Method A5): 2.09 min, [M+H]⁺=403.1; ¹H NMR (500MHz, CDCl₃) δ 8.86 (s, 2H), 7.78 (d, J=8.3 Hz, 1H), 7.57 (d, J=8.3 Hz,1H), 6.90 (s, 1H), 5.80 (s, 2H), 2.88 (q, J=7.4 Hz, 2H), 2.67 (s, 3H),2.57 (s, 3H), 1.40 (t, J=7.6 Hz, 3H).

Intermediate 188e:3-(2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-5-yl)-3′-methylbiphenyl-4-carbonitrile

A mixture of Intermediate 188d (25 mg, 0.062 mmol) and), m-tolylboronicacid (25.3 mg, 0.186 mmol) in THF (1 mL) was treated with 1.0 Mphosphoric acid, potassium salt (0.112 mL, 0.112 mmol) followed byPd-XPhos G3 (5.25 mg, 6.21 μmol). The resulting mixture was degassedwith N₂ for 2 min before the reaction vessel was sealed and irradiatedin a microwave reactor at 140° C. for 45 min. The cooled reactionmixture was concentrated to dryness and the residue purified by ISCO(Hexanes/AcOEt, 0-100%) to afford the title compound (Intermediate 188e,28 mg, 0.061 mmol, 98% yield) as a colorless oil. LC-MS (Method A5):2.41 min, [M+H]⁺=459.2; ¹H NMR (500 MHz, CDCl₃) δ 8.93 (s, 2H), 7.90 (d,J=8.0 Hz, 1H), 7.78 (dd, J=8.0, 1.7 Hz, 1H), 7.66 (d, J=1.7 Hz, 1H),7.48-7.37 (m, 3H), 7.34-7.23 (m, 1H), 6.91 (s, 1H), 5.82 (s, 2H), 2.91(q, J=7.7 Hz, 2H), 2.68 (s, 3H), 2.59 (s, 3H), 2.46 (s, 3H), 1.42 (t,J=7.6 Hz, 3H)

Example 188:2-ethyl-5,7-dimethyl-3-((5-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyrimidin-2-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 188e (28.4 mg, 0.062 mmol) in toluene (1.5mL) was added dibutyltin oxide (30.9 mg, 0.124 mmol) and TMS-N₃ (0.082mL, 0.620 mmol). Then the reaction vessel was sealed and the mixture washeated at 100° C. overnight behind a blast shield (according to theprocedure described in J. Org. Chem, 1993, 58, 4139). After cooling, thereaction mixture was concentrated, re-solvated in DMF, filtered thenpurified via preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 ACN: H₂O with 0.1% trifluoroacetic acid; Gradient:20-60% B over 23 minutes, then a 4-minute hold at 100% B; Flow: 20mL/min) to afford 19.5 mg (0.038 mmol, 61.4% yield) of the titlecompound Example 188. LC-MS (Method A3): 1.5 min, [M+H]⁺=502.21; ¹H NMR(500 MHz, DMSO-d₆) δ 8.63 (s, 2H), 7.95 (s, 2H), 7.85 (s, 1H), 7.66 (s,1H), 7.62 (br d, J=7.7 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.25 (br d,J=7.5 Hz, 1H), 6.92 (s, 1H), 5.70 (s, 2H), 3.05-2.67 (m, 2H), 2.53 (brs, 3H), 2.48 (s, 3H), 2.40 (s, 3H), 0.88 (br t, J=7.2 Hz, 3H).

The following examples have been similarly prepared from Intermediate188d as described above for Example 188. Two analytical LC-MS injectionswere used to determine the final purity. The retention time of one ofthem is reported for each compound and is referred as Method A3, MethodA4 or Method A5.

LC-MS m/z [M + H]⁺; RT; ¹H NMR (500 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 189

503.57 504.18; 1.2 min (Method A3) 8.61 (s, 2H), 7.88 (s, 2H), 7.71 (s,1H), 7.43 (br d, J = 7.6 Hz, 1H), 7.29-7.19 (m, 1H), 6.99 (d, J = 7.9Hz, 1H), 6.95-6.80 (m, 2H), 5.70 (s, 2H), 2.79 (q, J = 7.3 Hz, 2H), 2.52(br s, 3H), 2.47 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H) 190

487.57 488.04; 1.37 min (Method A3) 8.66 (s, 2H), 8.03-7.93 (m, 2H),7.90 (s, 1H), 7.85 (br d, J = 7.3 Hz, 2H), 7.60-7.47 (m, 2H), 7.48- 7.39(m, 1H), 6.93 (s, 1H), 5.71 (s, 2H), 2.81 (q, J = 7.6 Hz, 2H), 2.55 (s,3H), 2.47 (s, 3H), 1.29 (t, J = 7.3 Hz, 3H)

Example 191:2-ethyl-5,7-dimethyl-3-((6-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyridazin-3-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 191a:3-((6-bromopyridazin-3-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001c (200 mg, 1.141 mmol) in DMF (4.0 mL)was added sodium hydride (100 mg, 2.51 mmol) at RT and the reaction wasstirred vigorously for 30 min. Then a solution of3-bromo-6-(bromomethyl)pyridazine, hydrobromide (399 mg, 1.198 mmol) inDMF (1.6 mL) was added and the resulting reaction mixture was allowed tostir for 2 h before being quenched with a saturated aqueous solution ofNH₄Cl. The mixture was diluted with EtOAc and extracted. The organicphase was dried over MgSO₄, filtered and concentrated before beingpurified by ISCO (Hex/EtOAc, 0-100%) to afford the title compound(Intermediate 191a, 270 mg, 0.780 mmol, 68.3% yield) as a white solid.LC-MS (Method A5): 1.70 min, [M+H]⁺=346.0 and 348.0; ¹H NMR (500 MHz,CDCl₃) δ 7.57 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 6.93 (s, 1H),5.75 (s, 2H), 2.95 (q, J=7.5 Hz, 2H), 2.64 (s, 3H), 2.61 (s, 3H), 1.37(t, J=7.6 Hz, 3H).

Intermediate 191b:4-chloro-2-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridazin-3-yl)benzonitrile

A mixture of Intermediate 191a (100 mg, 0.289 mmol) and4-chloro-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile (94 mg,0.375 mmol) in THF (3 mL) was treated with 1.5 M Na₂CO₃ (0.578 mL, 0.866mmol) followed by PdCl₂(dppf) (11.79 mg, 0.014 mmol). The resultingmixture was degassed with N₂ for 2 min before the reaction vessel wassealed and irradiated in a microwave reactor at 125° C. for 75 min. Thecooled reaction mixture was diluted with DCM and extracted. The combinedorganic layer was washed with brine, dried over MgSO₄, and concentrated.The crude sample in 2 ml of DCM was treated with TEA (0.201 mL, 1.444mmol) followed by TFAA (0.061 mL, 0.433 mmol). The mixture was stirredat RT for 1 hour, then concentrated to dryness and the residue purifiedby ISCO (Hexanes/AcOEt, 0-100%) to afford the title compound(Intermediate 191b, 40 mg, 0.099 mmol, 34.4% yield) as an amber oil.LC-MS (Method A5): 2.04 min, [M+H]⁺=403.0; ¹H NMR (500 MHz, CDCl₃) δ8.06 (d, J=1.9 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H),7.65-7.55 (m, 2H), 6.95 (s, 1H), 5.89 (s, 2H), 3.01 (q, J=7.4 Hz, 2H),2.65 (s, 3H), 2.63 (s, 3H), 1.40 (t, J=7.6 Hz, 3H)

Intermediate 191c:3-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridazin-3-yl)-3′-methylbiphenyl-4-carbonitrile

A mixture of Intermediate 191b (40 mg, 0.099 mmol) and m-tolylboronicacid (40.5 mg, 0.298 mmol) in THF (1 mL) was treated with 1.0 Mphosphoric acid, potassium salt (0.179 mL, 0.179 mmol) followed byPd-XPhos G3 (8.40 mg, 9.93 μmol). The resulting mixture was degassedwith N₂ for 2 min before the reaction vessel was sealed and irradiatedin a microwave reactor at 140° C. for 60 min. The cooled reactionmixture was concentrated to dryness and the residue purified by ISCO(Hexanes/AcOEt, 0-100%) to afford the title compound (Intermediate 191c,35 mg, 0.076 mmol, 77% yield) as a colorless oil. LC-MS (Method A5):2.35 min, [M+H]⁺=459.1; ¹H NMR (500 MHz, CDCl₃) δ 8.26 (d, J=1.1 Hz,1H), 8.01 (d, J=8.8 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.83 (dd, J=8.0,1.4 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.52-7.45 (m, 2H), 7.40 (t, J=7.6Hz, 1H), 7.33-7.20 (m, 1H), 6.95 (s, 1H), 5.90 (s, 2H), 3.04 (q, J=7.5Hz, 2H), 2.66 (s, 3H), 2.64 (s, 3H), 2.46 (s, 3H), 1.41 (t, J=7.6 Hz,3H).

Example 191:2-ethyl-5,7-dimethyl-3-((6-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyridazin-3-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 191c (35 mg, 0.076 mmol) in toluene (1.5mL) was added dibutyltin oxide (38.0 mg, 0.153 mmol) and TMS-N₃ (0.101mL, 0.763 mmol). Then the reaction vessel was sealed and the mixture washeated at 100° C. overnight behind a blast shield (according to theprocedure described in J. Org. Chem, 1993, 58, 4139). After cooling, thereaction mixture was concentrated, re-solvated in DMF, filtered thenpurified via preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile PhaseB: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 15-55% B over 22 minutes,then a 6-minute hold at 100% B; Flow: 20 mL/min) to afford 18.2 mg(0.036 mmol, 46.7% yield) of the title compound Example 191. LC-MS(Method A3): 1.38 min, [M+H]⁺=502.26; ¹H NMR (500 MHz, DMSO-d₆) δ8.08-7.94 (m, 2H), 7.91 (d, J=7.9 Hz, 1H), 7.75 (d, J=8.9 Hz, 1H), 7.65(s, 1H), 7.61 (br d, J=7.6 Hz, 1H), 7.57 (d, J=8.5 Hz, 1H), 7.40 (t,J=7.6 Hz, 1H), 7.25 (br d, J=7.6 Hz, 1H), 6.96 (s, 1H), 5.78 (s, 2H),2.98-2.78 (m, 2H), 2.56 (s, 3H), 2.51 (br s, 3H), 2.39 (s, 3H), 1.28 (t,J=7.5 Hz, 3H).

Example 192:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(pyridin-2-yl)biphenyl-2-carboxylicacid

Intermediate 192a:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(methoxycarbonyl)biphenyl-3-ylboronicacid

To a pressure-rated vial containing Intermediate 181a (100 mg, 0.230mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane(10.99 mg, 0.023 mmol), Pd₂(dba)₃ (21.10 mg, 0.023 mmol) andbis(pinacolato)diboron (117 mg, 0.461 mmol) was added dioxane (2 ml)followed by KOAc (113 mg, 1.152 mmol). The reaction mixture was degassedwith N₂ for 2 min before the reaction vessel was sealed and heated at105° C. for 60 min. The mixture was cooled and filtered through celiteand purified via preparative HPLC (Column: Phenomenex AXIA Luna 100×30mm 5 u s; Mobile Phase A: 10:90 ACN: H₂O with 10 mM TFA; Mobile Phase B:90:10 ACN: H₂O with 10 mM TFA; Gradient: 0-100% B over 10 minutes, thena 2-minute hold at 100% B; Flow: 40 mL/min.) to afford the titlecompound (Intermediate 192a, 88 mg, 0.199 mmol, 86% yield). LC-MS(Method A5): 2.16 min, [M+H]⁺=444.1; ¹H NMR (500 MHz, MeOH-d₄) δ7.91-7.52 (m, 3H), 7.42-7.28 (m, 5H), 5.79 (s, 2H), 3.74-3.59 (m, 3H),3.23 (q, J=7.6 Hz, 2H), 2.72 (s, 3H), 2.68 (s, 3H), 1.39 (t, J=7.6 Hz,3H).

Example 192:4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(pyridin-2-yl)biphenyl-2-carboxylicacid

A mixture of Intermediate 192a (22 mg, 0.050 mmol) and 2-bromopyridine(23.52 mg, 0.149 mmol) in THF (1 mL) was treated with 1.0 M phosphoricacid, potassium salt (0.089 mL, 0.089 mmol) followed by Pd-XPhos G3(4.20 mg, 4.96 μmol). The resulting mixture was degassed with N₂ for 2min before the reaction vessel was sealed and irradiated in a microwavereactor at 130° C. for 30 min. The cooled reaction mixture was treatedwith MeOH (0.5 mL) and 2.0 M NaOH ((0.248 mL, 0.496 mmol). The mixturewas reheated in a microwave reactor at 100° C. for 1 hour. Aftercooling, the reaction mixture was concentrated, re-solvated in DMF,filtered then purified via preparative HPLC (Column: XBridge C18, 19×200mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc;Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 40-80% B over19 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min) to afford2.3 mg (0.005 mmol, 9.6% yield) of the title compound Example 192. LC-MS(Method A3): 1.14 min, [M+H]⁺=463.16. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67(br d, J=4.3 Hz, 1H), 8.07 (br dd, J=17.5, 8.1 Hz, 2H), 7.99 (s, 1H),7.89 (br t, J=7.6 Hz, 1H), 7.73 (br d, J=7.9 Hz, 1H), 7.40 (br d, J=7.6Hz, 3H), 7.16 (br d, J=7.9 Hz, 2H), 6.97 (s, 1H), 5.52 (s, 2H), 2.83 (q,J=7.3 Hz, 2H), 2.54 (s, 6H), 1.28 (t, J=7.3 Hz, 3H).

The following examples have been similarly prepared from Intermediate192a as described above for Example 192. Two analytical LC-MS injectionswere used to determine the final purity. The retention time of one ofthem is reported for each compound and is referred as Method A3, MethodA4 or Method A5.

LC-MS m/z [M + H]⁺; RT; ¹H NMR (500 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 193

476.58 477.21; 1.23 min (Method A1) 8.52 (d, J = 4.9 Hz, 1H), 8.13 (brd, J = 8.5 Hz, 1H), 8.00 (s, 1H), 7.93 (s, 1H), 7.84 (d, J = 7.9 Hz,1H), 7.36 (br d, J = 7.9 Hz, 2H), 7.25 (br d, J = 4.6 Hz, 1H), 7.21 (brd, J = 7.9 Hz, 2H), 7.04 (s, 1H), 5.56 (s, 2H), 2.92-2.83 (m, 2H), 2.55(br s, 3H), 2.54 (s, 3H), 2.39 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H) 194

490.61 491.26; 1.41 min (Method A3) 8.13 (br d, J = 8.2 Hz, 1H), 8.00(s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.73 (s, 1H), 7.36 (br d, J = 7.9 Hz,2H), 7.19 (br d, J = 7.6 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 5.53 (s,2H), 2.84 (q, J = 7.4 Hz, 2H), 2.56 (s, 3H), 2.54 (s, 3H), 2.49 (s, 3H),2.35 (s, 3H), 1.29 (t, J = 7.5 Hz, 3H).

Example 195:3-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-3-yl)-3′-methylbiphenyl-4-carboxylicacid

Intermediate 195a:4-bromo-2-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-3-yl)benzoicacid

A mixture of Intermediate 177c (crude boronic ester, 60 mg, 0.107 mmol)and 4-bromo-2-iodobenzoic acid (35.0 mg, 0.107 mmol) in NMP/H₂O (1:1, 1mL) was treated with K₂CO₃ (32.6 mg, 0.236 mmol) followed by Pd₂(dba)₃(9.80 mg, 10.71 mol). The resulting mixture was degassed with N₂ for 2min before the reaction vessel was sealed and irradiated in a microwavereactor at 120° C. for 15 min. The mixture was cooled and filteredthrough celite and purified via preparative HPLC (Column: PhenomenexAXIA Luna 100×30 mm 5 u s; Mobile Phase A: 10:90 ACN: H₂O with 10 mMTFA; Mobile Phase B: 90:10 ACN: H₂O with 10 mM TFA; Gradient: 0-100% Bover 10 minutes, then a 2-minute hold at 100% B; Flow: 40 mL/min.) toafford the title compound (Intermediate 195a, 17 mg, 0.037 mmol, 34.5%yield). LC-MS (Method A5): 2.27 min, [M+H]⁺=465.1 and 467.1. ¹H NMR (500MHz, CDCl₃) δ 7.91 (br d, J=8.0 Hz, 1H), 7.76 (br s, 1H), 7.65 (br d,J=7.7 Hz, 1H), 7.44 (br s, 2H), 5.84 (br s, 2H), 3.26 (br s, 2H),2.72-2.54 (m, 6H), 1.38 (br s, 3H).

Example 195:3-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-3-yl)-3′-methylbiphenyl-4-carboxylicacid

A mixture of Intermediate 195a (17 mg, 0.037 mmol) and m-tolylboronicacid (14.90 mg, 0.110 mmol) in THF (1 mL) was treated with 1.5 M Na₂CO₃(0.073 mL, 0.110 mmol) followed by PdCl₂(dppf) (2.98 mg, 3.65 mol). Theresulting mixture was degassed with N₂ for 2 min before the reactionvessel was sealed and irradiated in a microwave reactor at 135° C. for30 min After cooling, the reaction mixture was concentrated, re-solvatedin DMF, filtered then purified via preparative HPLC (Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mMNH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient:17-57% B over 20 minutes, then a 4-minute hold at 100% B; Flow: 20mL/min) to afford 7.8 mg (0.016 mmol, 44.8% yield) of the title compoundExample 195. LC-MS (Method A3): 1.44 min, [M+H]⁺=477.11; ¹H NMR (500MHz, DMSO-d₆) δ 8.50 (s, 1H), 7.87 (br d, J=8.2 Hz, 1H), 7.81 (br d,J=7.9 Hz, 1H), 7.75 (br d, J=7.6 Hz, 1H), 7.59 (s, 2H), 7.54 (br d,J=7.6 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 7.21 (br d, J=7.3 Hz, 1H), 7.18(d, J=8.2 Hz, 1H), 6.94 (s, 1H), 5.59 (s, 2H), 2.87 (q, J=7.3 Hz, 2H),2.52 (br s, 3H), 2.50 (br s, 3H), 2.37 (s, 3H), 1.29 (t, J=7.5 Hz, 3H).

Example 196:3-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-3-yl)-[1,1′-biphenyl]-4-carboxylicacid

Example 196 has been similarly prepared from Intermediate 195a asdescribed above for Example 195. LC-MS (Method A3): 1.42 min,[M+H]⁺=463.32; ¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.95 (d, J=7.9Hz, 1H), 7.81 (br d, J=7.9 Hz, 2H), 7.77 (br d, J=7.6 Hz, 2H), 7.63 (s,1H), 7.52-7.46 (m, 2H), 7.44-7.38 (m, 1H), 7.20 (br d, J=8.2 Hz, 1H),6.94 (s, 1H), 5.60 (s, 2H), 2.87 (q, J=7.4 Hz, 2H), 2.52 (br s, 3H),2.50 (br s, 3H), 1.29 (t, J=7.3 Hz, 3H).

Example 197:2-ethyl-5,7-dimethyl-3-((2-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyrimidin-5-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 197a: 2-bromo-5-(bromomethyl)pyrimidine

To a suspension of (2-chloropyrimidin-5-yl)methanol (330 mg, 2.283 mmol)in DCM (6.0 mL) was added a solution of PBr₃ (0.323 ml, 3.42 mmol) inDCM (0.3 mL) dropwise. The resulting mixture was stirred at RT forovernight. The mixture was concentrated under reduced pressure andpurified by ISCO (Hexanes/AcOEt, 0-100%) to afford the title compound(Intermediate 197a, 110 mg, 0.437 mmol, 19.13% yield) as a white solid.LC-MS (Method A5): 1.72 min, [M+H]⁺=252.8; ¹H NMR (500 MHz, MeOH-d₄) δ8.67 (s, 2H), 4.68 (s, 2H).

Intermediate 197b:3-((2-bromopyrimidin-5-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001c (69.6 mg, 0.397 mmol) in DMF (2.0 mL)was added sodium hydride (20.64 mg, 0.516 mmol)) at RT and the reactionwas stirred vigorously for 30 min. Then a solution of Intermediate 197a(100 mg, 0.397 mmol) in DMF (0.8 mL) was added and the resultingreaction mixture was allowed to stir for 2 h before being quenched witha saturated aqueous solution of NH₄Cl. The mixture was diluted withEtOAc and extracted. The organic phase was dried over MgSO₄, filteredand concentrated before being purified by ISCO (Hex/EtOAc, 0-100%) toafford the title compound (Intermediate 197b, 71 mg, 0.205 mmol, 51.7%yield) as a white solid. LC-MS (Method A5): 1.80 min, [M+H]⁺=346.0 and348.0; ¹H NMR (500 MHz, CDCl₃) δ 8.62 (s, 1H), 8.56 (s, 1H), 6.93 (s,1H), 5.42 (d, J=12.9 Hz, 2H), 2.89 (q, J=7.4 Hz, 2H), 2.64 (s, 3H), 2.59(d, J=1.1 Hz, 3H), 1.43 (t, J=7.6 Hz, 3H).

Intermediate 197c:4-chloro-2-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-2-yl)benzonitrile

A mixture of Intermediate 197b (70 mg, 0.202 mmol) and(5-chloro-2-cyanophenyl)boronic acid (47.7 mg, 0.263 mmol) in THF (3 mL)was treated with 1.5 M Na₂CO₃ (0.404 mL, 0.607 mmol) followed byPdCl₂(dppf) (16.51 mg, 0.020 mmol). The resulting mixture was degassedwith N₂ for 2 min before the reaction vessel was sealed and irradiatedin a microwave reactor at 130° C. for 75 min. The cooled reactionmixture was diluted with DCM and extracted. The combined organic layerwas washed with brine, dried over MgSO₄, and concentrated. The crudesample in 2 ml of DCM was treated with TEA (0.141 mL, 1.011 mmol)followed by TFAA (0.043 mL, 0.303 mmol). The mixture was stirred at RTfor 1 hour, then concentrated to dryness and the residue purified byISCO (Hexanes/AcOEt, 0-100%) to afford the title compound (Intermediate197c, 40 mg, 0.099 mmol, 49.1% yield) as an amber oil. LC-MS (MethodA5): 2.27 min, +=403.1.

Intermediate 197d:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-2-yl)-3′-methylbiphenyl-4-carbonitrile

A mixture of Intermediate 197c (20 mg, 0.050 mmol) m-tolylboronic acid(6.75 mg, 0.050 mmol) in THF (1 mL) was treated with 1.0 M phosphoricacid, potassium salt (0.089 mL, 0.089 mmol) followed by Pd-XPhos G3(4.20 mg, 4.96 μmol). The resulting mixture was degassed with N₂ for 2min before the reaction vessel was sealed and irradiated in a microwavereactor at 140° C. for 60 min. The cooled reaction mixture wasconcentrated to dryness and the residue purified by ISCO (Hexanes/AcOEt,0-100%) to afford the title compound (Intermediate 197d, 20 mg, 0.044mmol, 88%) as a colorless oil. LC-MS (Method A5): 2.49 min,[M+H]⁺=459.0; ¹H NMR (500 MHz, CDCl₃) δ 8.87 (s, 2H), 8.61 (d, J=1.9 Hz,1H), 7.91 (d, J=8.0 Hz, 1H), 7.79 (dd, J=8.1, 1.8 Hz, 1H), 7.53-7.47 (m,2H), 7.39 (t, J=7.6 Hz, 1H), 7.27 (d, J=7.7 Hz, 1H), 6.95 (s, 1H), 5.54(s, 2H), 2.93 (q, J=7.6 Hz, 2H), 2.66 (s, 3H), 2.63 (s, 3H), 2.46 (s,3H), 1.44 (t, J=7.6 Hz, 3H)

Example 197:2-ethyl-5,7-dimethyl-3-((2-(3′-methyl-4-(1H-tetrazol-5-yl)biphenyl-3-yl)pyrimidin-5-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 197d (20 mg, 0.044 mmol) in toluene (1.5mL) was added dibutyltin oxide (21.71 mg, 0.087 mmol) and TMS-N₃ (0.058mL, 0.436 mmol). Then the reaction vessel was sealed and the mixture washeated at 100° C. overnight behind a blast shield (according to theprocedure described in J. Org. Chem, 1993, 58, 4139). After cooling, thereaction mixture was concentrated, re-solvated in DMF, filtered thenpurified via preparative HPLC (Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile PhaseB: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 15-55% B over 20 minutes,then a 4-minute hold at 100% B; Flow: 20 mL/min) to afford 17.8 mg(0.035 mmol, 81% yield) of the title compound Example 197. LC-MS (MethodA3): 1.44 min, [M+H]⁺=502.04; ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 2H),8.15 (s, 1H), 7.93 (br d, J=7.9 Hz, 1H), 7.84 (d, J=7.9 Hz, 1H),7.67-7.51 (m, 2H), 7.40 (t, J=7.6 Hz, 1H), 7.25 (br d, J=7.3 Hz, 1H),6.98 (s, 1H), 5.53 (s, 2H), 2.92 (q, J=7.4 Hz, 2H), 2.56 (s, 3H), 2.54(s, 3H), 2.40 (s, 3H), 1.31 (t, J=7.5 Hz, 3H).

Example 198:3-(2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-5-yl)-3′-methylbiphenyl-4-carboxylicacid

Intermediate 198a: methyl4-chloro-2-(2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-5-yl)benzoate

A mixture of(24(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-5-yl)boronicacid (Intermediate 188c, 45 mg, 0.145 mmol) and methyl4-chloro-2-iodobenzoate (40 mg, 0.135 mmol) in THF (1.5 mL) was treatedwith 1.5 M Na₂CO₃ (0.270 mL, 0.405 mmol) followed by PdCl₂(dppf) (5.51mg, 6.75 μmol). The resulting mixture was degassed with N₂ for 2 minbefore the reaction vessel was sealed and irradiated in a microwavereactor at 100° C. for 30 min. The cooled reaction mixture was dilutedwith DCM and extracted. The combined organic layer was washed withbrine, dried over MgSO₄, and concentrated to dryness and the residuepurified by ISCO (Hexanes/AcOEt, 0-100%) to afford the title compound(Intermediate 198a, 36 mg, 0.083 mmol, 61.2% yield) as a yellow oil.LC-MS (Method A5): 2.20 min, [M+H]⁺=436.1; ¹H NMR (500 MHz, CDCl₃) δ8.59 (s, 1H), 8.67-8.44 (m, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.52 (dd,J=8.5, 2.2 Hz, 1H), 6.90 (s, 1H), 5.78 (s, 2H), 3.72 (s, 3H), 2.87 (q,J=7.7 Hz, 2H), 2.67 (s, 3H), 2.59 (s, 3H), 1.39 (t, J=7.6 Hz, 3H)

Example 198:3-(2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-5-yl)-3′-methylbiphenyl-4-carboxylicacid

A mixture of methyl4-chloro-2-(2-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-5-yl)benzoate(Intermediate 198a, 18 mg, 0.041 mmol) and m-tolylboronic acid (16.84mg, 0.124 mmol) in THF (1 mL) was treated with 1.0 M phosphoric acid,potassium salt (0.074 mL, 0.074 mmol) followed by Pd-XPhos G3 (1.748 mg,2.065 μmol). The resulting mixture was degassed with N₂ for 2 min beforethe reaction vessel was sealed and irradiated in a microwave reactor at140° C. for 45 min. The cooled reaction mixture was treated with MeOH(0.5 mL) and 2.0 M NaOH (0.124 mL, 0.248 mmol). The mixture was reheatedin a microwave reactor at 100° C. for 30 min After cooling, the reactionmixture was concentrated, re-solvated in DMF, filtered then purified viapreparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid; Mobile Phase B:95:5 ACN: H₂O with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 19minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.) to afford10.6 mg (0.022 mmol, 53.8% yield) of the title compound Example 198.LC-MS (Method A3): 1.42 min, [M+H]⁺=478.35; ¹H NMR (500 MHz, DMSO-d₆) δ8.76 (s, 2H), 8.05 (d, J=8.2 Hz, 1H), 7.85 (br d, J=7.6 Hz, 1H), 7.70(s, 1H), 7.62 (s, 1H), 7.58 (br d, J=7.4 Hz, 1H), 7.37 (t, J=7.6 Hz,1H), 7.24 (br d, J=7.4 Hz, 1H), 6.92 (s, 1H), 5.72 (s, 2H), 2.84 (q,J=7.5 Hz, 2H), 2.55 (s, 3H), 2.48 (s, 3H), 2.39 (s, 3H), 1.31 (t, J=7.4Hz, 3H).

Example 199:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)-3′-methylbiphenyl-4-carboxylicacid

Intermediate 199a: ethyl4-chloro-2-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)benzoate

A mixture Intermediate 186b (40 mg, 0.116 mmol) and(5-chloro-2-(ethoxycarbonyl)phenyl)boronic acid (31.7 mg, 0.139 mmol) inTHF (1.5 mL) was treated with 1.5 M Na₂CO₃ (0.231 mL, 0.347 mmol)followed by PdCl₂(dppe (9.43 mg, 0.012 mmol). The resulting mixture wasdegassed with N₂ for 2 min before the reaction vessel was sealed andirradiated in a microwave reactor at 125° C. for 45 min. The cooledreaction mixture was diluted with DCM and extracted. The combinedorganic layer was washed with brine, dried over MgSO₄, and concentratedto dryness and the residue purified by ISCO (Hexanes/AcOEt, 0-100%) toafford the title compound (Intermediate 199a, 44 mg, 0.098 mmol, 85%yield) as an amber oil. LC-MS (Method A5): 2.23 min, [M+H]⁺=450.1; ¹HNMR (500 MHz, CDCl₃) δ 8.60 (d, J=8.5 Hz, 2H), 7.90 (d, J=8.8 Hz, 1H),7.54-7.47 (m, 2H), 6.91 (s, 1H), 5.65 (s, 2H), 4.21-4.06 (m, 2H), 3.02(q, J=7.4 Hz, 2H), 2.64 (s, 3H), 2.60 (s, 3H), 1.44 (t, J=7.6 Hz, 3H)

Example 199:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)-3′-methylbiphenyl-4-carboxylicacid

A mixture of ethyl4-chloro-2-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrazin-2-yl)benzoate(Intermediate 199a, 44 mg, 0.098 mmol) and m-tolylboronic acid (39.9 mg,0.293 mmol) in THF (1 mL) was treated with 1.0 M phosphoric acid,potassium salt (0.176 mL, 0.176 mmol) followed by Pd-XPhos G3 (8.28 mg,9.78 mol). The resulting mixture was degassed with N₂ for 2 min beforethe reaction vessel was sealed and irradiated in a microwave reactor at140° C. for 45 min. The cooled reaction mixture was treated with MeOH(0.5 mL) and 2.0 M NaOH (0.293 mL, 0.587 mmol). The mixture was reheatedin a microwave reactor at 100° C. for 30 min After cooling, the reactionmixture was concentrated, re-solvated in DMF, filtered then purified viapreparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 ACN: H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂Owith 10 mM NH₄OAc; Gradient: 10-50% B over 20 minutes, then a 5-minutehold at 100% B; Flow: 20 mL/min.) to afford 13.3 mg (0.027 mmol, 27.3%yield) of the title compound Example 199. LC-MS (Method A3): 1.4 min,[M+H]⁺=478.22; ¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.70 (s, 1H),7.94-7.87 (m, 1H), 7.86-7.76 (m, 2H), 7.60 (s, 1H), 7.56 (br d, J=7.6Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.24 (br d, J=7.3 Hz, 1H), 6.95 (s,1H), 5.69 (s, 2H), 2.93 (q, J=7.6 Hz, 2H), 2.56 (s, 3H), 2.50 (s, 3H),2.38 (s, 3H), 1.32 (t, J=7.5 Hz, 3H).

Example 200:3-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridazin-3-yl)-3′-methylbiphenyl-4-carboxylicacid

Intermediate 200a: ethyl4-chloro-2-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridazin-3-yl)benzoate

A mixture of Intermediate 191a (50 mg, 0.144 mmol) and(5-chloro-2-(ethoxycarbonyl)phenyl)boronic acid (39.6 mg, 0.173 mmol) inTHF (1.5 mL) was treated with 1.5 M Na₂CO₃ (0.289 mL, 0.433 mmol))followed by PdCl₂(dppf) (11.79 mg, 0.014 mmol). The resulting mixturewas degassed with N₂ for 2 min before the reaction vessel was sealed andirradiated in a microwave reactor at 125° C. for 45 min. The cooledreaction mixture was diluted with DCM and extracted. The combinedorganic layer was washed with brine, dried over MgSO₄, and concentratedto dryness and the residue purified by ISCO (Hexanes/AcOEt, 0-100%) toafford the title compound (Intermediate 200a, 40 mg, 0.089 mmol, 61.6%yield) as an amber oil. LC-MS (Method A5): 2.19 min, [M+H]⁺=450.1; ¹HNMR (500 MHz, CDCl₃) δ 7.97 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 7.54 (br d,J=2.2 Hz, 1H), 7.48 (d, J=0.8 Hz, 2H), 6.93 (s, 1H), 5.85 (s, 2H), 4.14(q, J=7.2 Hz, 2H), 3.01 (q, J=7.4 Hz, 2H), 2.65 (s, 3H), 2.62 (s, 3H),1.39 (t, J=7.4 Hz, 3H), 1.06 (t, J=7.2 Hz, 3H)

Example 200:3-(6-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridazin-3-yl)-3′-methylbiphenyl-4-carboxylicacid

A mixture of Intermediate 200a (20 mg, 0.044 mmol) and m-tolylboronicacid (18.13 mg, 0.133 mmol) in THF (1 mL) was treated with 1.0 Mphosphoric acid, potassium salt (0.080 mL, 0.080 mmol) followed byPd-XPhos G3 (3.76 mg, 4.45 μmol). The resulting mixture was degassedwith N₂ for 2 min before the reaction vessel was sealed and irradiatedin a microwave reactor at 140° C. for 45 min. The cooled reactionmixture was treated with MeOH (0.5 mL) and 2.0 M NaOH (0.133 mL, 0.267mmol). The mixture was reheated in a microwave reactor at 100° C. for 1hour. After cooling, the reaction mixture was concentrated, re-solvatedin DMF, filtered then purified via preparative HPLC (Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂O with 0.1%trifluoroacetic acid; Gradient: 19-59% B over 20 minutes, then a4-minute hold at 100% B; Flow: 20 mL/min.) to afford 14.5 mg (0.032mmol, 71.8% yield) of the title compound Example 200. LC-MS (Method A3):1.35 min, [M+H]⁺=478.1; ¹H NMR (500 MHz, DMSO-d₆) δ 8.01-7.92 (m, 2H),7.92-7.87 (m, 1H), 7.82 (s, 1H), 7.65 (d, J=8.7 Hz, 1H), 7.62 (s, 1H),7.58 (br d, J=7.7 Hz, 1H), 7.38 (t, J=7.6 Hz, 1H), 7.25 (br d, J=7.4 Hz,1H), 6.99 (s, 1H), 5.83 (s, 2H), 2.92 (q, J=7.4 Hz, 2H), 2.53 (s, 3H),2.51 (s, 3H), 2.38 (s, 3H), 1.30 (t, J=7.4 Hz, 3H)

Example 201:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)biphenyl-4-carboxylicacid

Intermediate 201a: neopentyl4-bromo-2-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)benzoate

A mixture of Intermediate 039a (50 mg, 0.145 mmol) and(5-bromo-2-((neopentyloxy)carbonyl)phenyl)boronic acid (59.3 mg, 0.188mmol) in THF (1.5 mL) was treated with 1.5 M Na₂CO₃ (0.290 mL, 0.434mmol) followed by PdCl₂(dppf) (11.83 mg, 0.014 mmol). The resultingmixture was degassed with N₂ for 2 min before the reaction vessel wassealed and irradiated in a microwave reactor at 130° C. for 30 min. Thecooled reaction mixture was diluted with DCM and extracted. The combinedorganic layer was washed with brine, dried over MgSO₄, and concentratedto dryness and the residue purified by ISCO (Hexanes/AcOEt, 0-100%) toafford the title compound (Intermediate 201a, 20 mg, 0.037 mmol, 25.8%yield) as an amber oil. LC-MS (Method A5): 2.51 min, [M+H]⁺=535.2 and537.2; ¹H NMR (500 MHz, CDCl₃) δ 8.63 (d, J=1.4 Hz, 1H), 7.72 (d, J=8.3Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.62 (dd, J=8.3, 1.9 Hz, 1H), 7.56 (dd,J=8.1, 2.1 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 6.93 (s, 1H), 5.51 (s, 2H),3.74 (s, 2H), 2.89 (q, J=7.7 Hz, 2H), 2.65 (s, 3H), 2.62 (s, 3H), 1.42(t, J=7.6 Hz, 3H), 0.71 (s, 9H).

Example 201:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)biphenyl-4-carboxylicacid

A mixture of Intermediate 201a (20 mg, 0.037 mmol) and phenylboronicacid (13.66 mg, 0.112 mmol) in THF (1.5 mL) was treated with 1.5 MNa₂CO₃ (0.075 mL, 0.112 mmol) followed by PdCl₂(dppf) (3.05 mg, 3.73mol). The resulting mixture was degassed with N₂ for 2 min before thereaction vessel was sealed and irradiated in a microwave reactor at 130°C. for 30 min. The cooled reaction mixture was treated with MeOH (0.5mL) and 2.0 M NaOH (0.131 mL, 0.261 mmol). The mixture was reheated in amicrowave reactor at 100° C. for 15 min After cooling, the reactionmixture was concentrated, re-solvated in DMF, filtered then purified viapreparative HPLC (Column: XBridge C18, 19×200 mm, 5-μm particles; MobilePhase A: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid; Mobile Phase B:95:5 ACN: H₂O with 0.1% trifluoroacetic acid; Gradient: 15-55% B over 19minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min.) to afford 7.6mg (0.016 mmol, 41.3% yield) of the title compound Example 201. LC-MS(Method A3): 1.37 min, [M+H]⁺=463.31; ¹H NMR (500 MHz, DMSO-d₆) δ 8.52(s, 1H), 7.83-7.79 (m, 2H), 7.78 (s, 1H), 7.75 (br d, J=7.5 Hz, 2H),7.64 (s, 2H), 7.51-7.47 (m, 2H), 7.44-7.39 (m, 1H), 6.99 (s, 1H), 5.57(s, 2H), 2.89 (q, J=7.4 Hz, 2H), 2.55 (s, 3H), 2.53 (s, 3H), 1.29 (t,J=7.4 Hz, 3H).

Example 202:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-2-yl)-3′-methylbiphenyl-4-carboxylicacid

Intermediate 202a: 5-(bromomethyl)-2-chloropyrimidine

2-chloro-5-methylpyrimidine (200 mg, 1.556 mmol) was dissolved in carbontetrachloride (5 mL), NBS (332 mg, 1.867 mmol) and benzoyl peroxide(18.84 mg, 0.078 mmol) were added, and the resulting mixture was heatedand refluxed for overnight. The reaction solution was returned to RT,concentrated under reduced pressure and purified by ISCO (Hexanes/AcOEt,0-100%) to afford the title compound (Intermediate 202a, 116 mg, 0.559mmol, 35.9% yield) as a white solid. LC-MS (Method A5): 1.62 min,[M+H]⁺=206.9 and 208.9; ¹H NMR (500 MHz, CDCl₃) δ 8.69 (s, 2H), 4.44 (s,2H).

Intermediate 202b:3-((2-chloropyrimidin-5-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a solution of Intermediate 001c (90 mg, 0.514 mmol) in DMF (2.0 mL)was added sodium hydride (26.7 mg, 0.668 mmol) at RT and the reactionwas stirred vigorously for 30 min. Then a solution of Intermediate 202a(112 mg, 0.539 mmol) in DMF (0.8 mL) was added and the resultingreaction mixture was allowed to stir for 2 h before being quenched witha saturated aqueous solution of NH₄C₁. The mixture was diluted withEtOAc and extracted. The organic phase was dried over MgSO₄, filteredand concentrated before being purified by ISCO (Hex/EtOAc, 0-100%) toafford the title compound (Intermediate 202b, 87 mg, 0.288 mmol, 56.1%yield) as a white solid. LC-MS (Method A5): 1.79 min, [M+H]⁺=302.2; ¹HNMR (500 MHz, CDCl₃) δ 8.60 (s, 2H), 6.92 (s, 1H), 5.42 (s, 2H), 2.88(q, J=7.6 Hz, 2H), 2.62 (s, 3H), 2.58 (s, 3H), 1.41 (t, J=7.6 Hz, 3H).

Intermediate 202c:2-ethyl-3-((2-iodopyrimidin-5-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

HI (306 μl, 2.320 mmol) precooled to 0° C. was added to3-((2-chloropyrimidin-5-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(70 mg, 0.232 mmol) in a small vial. The mixture was kept and vigorouslystirred at 0° C. for 50 min. The light brownish green suspension wasquickly neutralized at 0° C. with a saturated aqueous solution ofpotassium carbonate and decolorized with potassium disulfite at 0° C.The aqueous solution was extracted with diethyl ether, dried overdesiccated MgSO₄, filtered, and evaporated under reduced pressure. Thecrude sample was purified by ISCO (Hexanes/AcOEt, 0-100%) to afford thetitle compound (Intermediate 202c, 30 mg, 0.076 mmol, 32.9% yield).LC-MS (Method A5): 1.89 min, [M+H]⁺=394.0; ¹H NMR (500 MHz, CDCl₃) δ8.45 (s, 2H), 6.92 (s, 1H), 5.38 (s, 2H), 2.88 (q, J=7.5 Hz, 2H), 2.63(s, 3H), 2.58 (s, 3H), 1.42 (t, J=7.6 Hz, 3H)

Intermediate 202d

A mixture of Intermediate 202c (30 mg, 0.076 mmol) and(5-chloro-2-(ethoxycarbonyl)phenyl)boronic acid (20.91 mg, 0.092 mmol)in THF (1.5 mL) was treated with 1.5 M Na₂CO₃ (0.153 mL, 0.229 mmol)followed by PdCl₂(dppf) (6.23 mg, 7.63 mol). The resulting mixture wasdegassed with N₂ for 2 min before the reaction vessel was sealed andirradiated in a microwave reactor at 125° C. for 30 min. The cooledreaction mixture was diluted with DCM and extracted. The combinedorganic layer was washed with brine, dried over MgSO₄, and concentratedto dryness and the residue purified by ISCO (DCM/MeOH, 0-20%) to affordthe title compound (Intermediate 202d, 22 mg, 0.049 mmol, 64.1% yield)as an amber oil. LC-MS (Method A5): 2.29 min, +=450.1; ¹H NMR (500 MHz,CDCl₃) δ 8.76 (s, 2H), 7.98 (d, J=1.9 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H),7.49 (dd, J=8.3, 1.9 Hz, 1H), 6.94 (s, 1H), 5.50 (s, 2H), 4.19 (q, J=7.2Hz, 2H), 2.93 (q, J=7.7 Hz, 2H), 2.65 (s, 3H), 2.61 (s, 3H), 1.44 (t,J=7.4 Hz, 3H), 1.09 (t, J=7.2 Hz, 3H)

Example 202:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyrimidin-2-yl)-3′-methylbiphenyl-4-carboxylicacid

A mixture of Intermediate 202d (20 mg, 0.044 mmol) and m-tolylboronicacid (18.13 mg, 0.133 mmol) in THF (1 mL) was treated with 1.0 Mphosphoric acid, potassium salt (0.080 mL, 0.080 mmol) followed byPd-XPhos G3 (3.76 mg, 4.45 mol). The resulting mixture was degassed withN₂ for 2 min before the reaction vessel was sealed and irradiated in amicrowave reactor at 140° C. for 45 min. The cooled reaction mixture wastreated with MeOH (0.5 mL) and 2.0 M NaOH (0.133 mL, 0.267 mmol). Themixture was reheated in a microwave reactor at 100° C. for 30 min Aftercooling, the reaction mixture was concentrated, re-solvated in DMF,filtered then purified via preparative HPLC (Column: XBridge C18, 19×200mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc;Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 15-55% B over25 minutes, then a 6-minute hold at 100% B; Flow: 20 mL/min) to afford8.5 mg (0.018 mmol, 39.5% yield) of the title compound Example 202.LC-MS (Method A3): 1.4 min, [M+H]⁺=478.06; ¹H NMR (500 MHz, DMSO-d₆) δ8.82 (s, 2H), 8.06 (d, J=1.6 Hz, 1H), 7.84 (dd, J=8.0, 1.7 Hz, 1H),7.79-7.71 (m, 1H), 7.55 (s, 1H), 7.52 (br d, J=7.7 Hz, 1H), 7.38 (t,J=7.6 Hz, 1H), 7.24 (br d, J=7.4 Hz, 1H), 7.02 (s, 1H), 5.60 (s, 2H),2.98 (q, J=7.3 Hz, 2H), 2.56 (br s, 3H), 2.54 (s, 3H), 2.39 (s, 3H),1.33 (t, J=7.4 Hz, 3H).

Example 203:3-(5-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)pyridin-2-yl)-3′-methyl-[1,1′-biphenyl]-4-carboxylicacid

Example 203 has been similarly prepared from Intermediate 201^(a) asdescribed above for Example 201. LC-MS (Method A3): 1.63 min,[M+H]⁺=477.16; ¹H NMR (500 MHz, DMSO-d₆) δ 7.89-7.64 (m, 4H), 7.60 (brs, 1H), 7.56 (br d, J=7.3 Hz, 1H), 7.38 (br t, J=7.5 Hz, 1H), 7.30-7.18(m, 2H), 7.12-6.94 (m, 2H), 5.66 (br s, 2H), 2.96 (br d, J=4.6 Hz, 2H),2.52 (br s, 6H), 2.38 (s, 3H), 1.30 (br s, 3H).

Example 204: 2-Ethyl-5,7-dimethyl-3-((5′-phenoxy-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 204a: 2-Bromo-4-phenoxybenzonitrile

To a solution of 2-bromo-4-fluorobenzonitrile (0.400 g, 2.000 mmol) andphenol (0.207 g, 2.200 mmol) in DMF (10 mL) was added potassiumcarbonate (0.332 g, 2.400 mmol) and the resulting mixture was stirred at50° C. in a sealed vial overnight. After 16 h, LC-MS showed that thereaction was essentially complete (co-injection with starting material),with a single major peak (target mass not observed). The mixture wasfiltered to remove the potassium salts, the filter-cake was washed witha DMF (2 mL) and the filtrate was evaporated. The residue obtained waspartitioned with EtOAc-saturated aqueous NH₄Cl and the organic phase wasseparated, dried (Na₂SO₄) and evaporated. This afforded the essentiallypure product (0.466 g, 85% yield) which was used as such in the nextstep. LC-MS (Method J): 1.330 min, +=no ion observed; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.90 (d, J=9.0 Hz, 1H), 7.48 (t, J=8.2 Hz, 1H), 7.39 (d,J=2.3 Hz, 1H), 7.29 (t, J=7.4 Hz, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.05 (dd,J=2.3, 8.6 Hz, 1H).

Intermediate 204b:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carbonitrile

A mixture of Intermediate 001d (0.060 g, 0.153 mmol), Intermediate 204a(0.053 g, 0.192 mmol) and 2 M Na₂CO₃ (0.192 mL, 0.383 mmol) intoluene-ethanol (9:1, 5 mL) was purged with a stream of N₂ for 5 min ina sealable vial. To this mixture was added Pd (Ph₃P)₄ (0.018 g, 0.015mmol), the vial was sealed and the mixture was stirred at 95° C. (blocktemperature) for 3 h. The cooled mixture was diluted with EtOAc and theorganic phase was separated, dried (Na₂SO₄) and evaporated to give agolden yellow gum. This material was purified by flash chromatography(ISCO/0-100% EtOAc-DCM) to give4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carbonitrile(0.041 g, 58.3% yield) as a colourless gum. This gum was lyophilizedfrom ACN-H₂O to give a white solid which was used as such in the nextstep. LC-MS (Method J): 1.479 min, [M+H]⁺=459.1; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.90 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.45 (m,2H), 7.27-7.21 (m, 3H), 7.17 (m, 2H), 7.08 (d, J=2.7 Hz, 1H), 7.02 (dd,J=2.7, 8.6 Hz, 1H), 6.94 (s, 1H), 5.51 (s, 2H), 2.78 (q, J=7.4 Hz, 2H),2.50 (s, 3H), 2.48 (hidden, 3H), 1.23 (t, J=7.4 Hz, 3H).

Example 204: 2-Ethyl-5,7-dimethyl-3-((5′-phenoxy-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a mixture of4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carbonitrile(0.012 g, 0.026 mmol), TMS-N₃ (0.037 mL, 0.262 mmol) and dibutyltinoxide (0.013 g, 0.052 mmol) was added toluene (2 mL). The vial wasbriefly purged with N₂ and then it was sealed and the mixture wasstirred at 120° C. (block temperature) for 16 h. The cooled mixture wasevaporated and the residual gum was taken up in DMF (acidified with a 10drops of AcOH) and filtered using a 0.45 μm syringe filter. The filtratewas submitted to preparative LC (Method D) and the product-containingfractions were combined and evaporated to give a white solid. Thismaterial was lyophilized from ACN-H₂O to give2-ethyl-5,7-dimethyl-3-((5′-phenoxy-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine(0.005 g, 38.1% yield) as a white solid.

LC-MS (Method J): 1.547 min, [M+H]⁺=502.1; ¹H NMR (400 MHz, DMSO-d₆) δppm 7.63 (d, J=8.6 Hz, 1H), 7.43 (t, J=8.6 Hz, 2H), 7.20 (t, J=7.4 Hz,1H), 7.14 (d, J=7.4 Hz, 2H), 7.09 (dd, J=2.3, 8.6 Hz, 1H), 7.03 (d,J=2.7 Hz, 1H), 7.01 (s, 4H), 6.92 (s, 1H), 5.41 (s, 2H), 2.72 (q, J=7.4Hz, 2H), 2.48 (hidden, 6H), 1.19 (t, J=7.4 Hz, 3H).

Example 205:2-Ethyl-3-((5′-(2-fluorophenoxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 205a:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile

A mixture of2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(001d, 0.262 g, 0.670 mmol), 2-bromo-4-fluorobenzonitrile (0.147 g,0.736 mmol) and 2 M Na₂CO₃ (0.837 mL, 1.674 mmol) in toluene-ethanol(9:1, 10 mL) was purged with a stream of N₂ for 5 min in a sealablevial. To this mixture was added Pd (Ph₃P)₄ (0.077 g, 0.067 mmol), thevial was sealed and the mixture was stirred at 95° C. (blocktemperature) for 2 h. The cooled mixture was diluted with EtOAc and theorganic phase was separated, dried (Na₂SO₄) and evaporated to give apale yellow gum. This material was purified by flash chromatography(ISCO/0-100% EtOAc-DCM) to give4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile(0.174 g, 67.6% yield) as a colourless gum which solidified on standingin vacuo to give a waxy solid. This material was used as such in thenext step. LC-MS (Method J): 1.331 min, [M+H]⁺=385.1; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.03 (dd, J=5.5, 8.6 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H),7.50 (dd, J=2.7, 9.8 Hz, 1H), 7.43 (dt, J=2.7, 8.6 Hz, 1H), 7.25 (d,J=8.2 Hz, 2H), 6.94 (s, 1H), 5.53 (s, 2H), 2.80 (q, J=7.4 Hz, 2H), 2.50(s, 3H), 2.49 (s, 3H), 1.23 (t, J=7.4 Hz, 3H).

Intermediate 205b: 4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-[1,1′-biphenyl]-2-carbonitrile

To a solution of4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile(0.025 g, 0.065 mmol) and 2-fluorophenol (8.02 mg, 0.072 mmol) in DMF (1mL) was added potassium carbonate (10.78 mg, 0.078 mmol) and theresulting mixture was stirred at 90° C. (block temperature) in a sealedvial for 16 h. The cooled mixture was filtered through a small plug ofcotton wool to remove the potassium salts and the residue was washedwith a little DMF. The filtrate was evaporated to give a pale purple gumwhich was purified by flash chromatography (ISCO/0-100% EtOAc-DCM) togive a colourless gum. This material was lyophilized from ACN-H₂O togive4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-[1,1′-biphenyl]-2-carbonitrile(0.026 g, 84% yield) as a white solid which was used as such in the nextstep. LC-MS (Method J): 1.439 min, [M+H]⁺=477.1; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.91 (d, J=8.6 Hz, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.45-7.26(m, 4H), 7.22 (d, J=8.2 Hz, 2H), 7.11 (d, J=2.7 Hz, 1H), 7.01 (dd,J=2.3, 8.6 Hz, 1H), 6.94 (s, 1H), 5.51 (s, 2H), 2.79 (q, J=7.4 Hz, 2H),2.50 (s, 3H), 2.48 (hidden, 3H), 1.23 (t, J=7.4 Hz, 3H).

Example 205:2-Ethyl-3-((5′-(2-fluorophenoxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a sealable vial containing4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-[1,1′-biphenyl]-2-carbonitrile(0.012 g, 0.025 mmol) and dibutyltin oxide (0.013 g, 0.050 mmol) intoluene (2 mL) was added TMS-N₃ (0.033 mL, 0.252 mmol). The vial wasthen sealed and the mixture were stirred at 100° C. (block temperature)for 18 h. Another portion of dibutyltin oxide (0.013 g, 0.050 mmol) andTMS-N₃ (0.033 mL, 0.252 mmol) was added and the mixture was heated at120° C. for an additional 18 h. The cooled mixture was evaporated andthe residue was taken up in DMF (1.8 mL, acidified with 10 drops ofAcOH) and submitted to purification by preparative LC (Method D). Theproduct-containing fractions were combined and evaporated to give a paleyellow-brown glass. This material was lyophilized from ACN-H₂O to give2-ethyl-3-((5′-(2-fluorophenoxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(0.013 g, 99% yield) as a beige solid. LC-MS (Method J): 1.341 min,[M+H]⁺=520.1; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.62 (d, J=8.6 Hz, 1H),7.44-7.31 (m, 2H), 7.27 (m, 2H), 7.07-7.02 (m, 2H), 7.01 (s, 4H), 6.92(s, 1H), 5.41 (s, 2H), 2.72 (q, J=7.4 Hz, 2H), 2.48 (hidden, 6H) 1.19(t, J=7.4 Hz, 3H).

The following examples have been similarly prepared from4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile(Intermediate 205a) as described above for Example 205. Two analyticalLC injections were used to determine the final purity. The retentiontime of one of them is reported for each compound and is referred asMethod J.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 206

536.03 536.1; 1.426 min (Method J) 7.64 (d, J = 8.2 Hz, 1H), 7.43 (t, J= 8.2 Hz, 1H), 7.26-7.21 (m, 2H),7.14 (dd, J = 2.3, 8.2 Hz, 1H),7.11-7.08 (m, 2H), 7.01 (m, 4H), 6.92 (s, 1H), 5.41 (s, 2H), 2.73 (q, J= 7.4 Hz, 2H), 2.48 (hidden, 6H), 1.19 (t, J = 7.4 Hz, 3H). 207

585.58 586.1; 1.438 min (Method J) 7.66 (d, J = 8.2 Hz, 1H), 7.53 (t, J= 8.2 Hz, 1H), 7.19-7.12 (m, 5H), 7.01 (m, 4H), 6.92 (s, 1H), 5.41 (s,2H), 2.72 (q, J = 7.4 Hz, 2H), 2.48 (hidden, 6H), 1.19 (t, J = 7.4 Hz,3H). 208

537.56 538.2; 1.387 min (Method J) 7.58 (d, J = 8.6 Hz, 1H), 7.49 (ddd,J = 3.1, 9.0, 11.7 Hz, 1H), 7.41 (dt, J = 5.5, 9.0 Hz, 1H), 7.14 (m,1H), 7.02 (m, 1H), 7.00 (m, 5H), 6.92 (s, 1H), 5.40 (s, 2H), 2.73 (q, J= 7.4 Hz, 2H), 2.48 (hidden, 6H), 1.20 (t, J = 7.4 Hz, 1H).

Example 209:3-((5′-(Cyclohexyloxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 209a: 2-Bromo-4-(cyclohexyloxy)benzonitrile

A mixture of 2-bromo-4-fluorobenzonitrile (0.400 g, 2.000 mmol),cyclohexanol (0.458 mL, 4.400 mmol) and potassium carbonate (0.664 g,4.800 mmol) in DMF (10 mL) was reacted according to the method describedfor the preparation of Intermediate 204a. This afforded2-bromo-4-(cyclohexyloxy)benzonitrile (0.042 g, 8.0% yield)) as a whitesolid which was used as such in the next step. LC-MS (Method J): 1.396min, +=no ion observed; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.80 (d, J=8.6Hz, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.11 (dd, J=2.3, 8.6 Hz, 1H), 4.54 (m,1H), 1.88 (m, 2H), 1.69 (m, 2H), 1.50 (m, 1H), 1.46-1.33 (m, 4H), 1.25(m, 1H).

Intermediate 209b:5-(Cyclohexyloxy)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

A mixture of2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(001d, 0.056 g, 0.143 mmol), 2-bromo-4-(cyclohexyloxy)-benzonitrile(0.040 g, 0.143 mmol) was reacted according to the method described forthe preparation of Intermediate 204b. This afforded5-(cyclohexyloxy)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.044 g, 66.2% yield) as a colourless gum. This gum was lyophilizedfrom ACN-H₂O to give a white solid which was used as such in the nextstep. LC-MS (Method J): 1.577 min, [M+H]⁺=465.1; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.78 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.2 Hz, 2H), 7.22 (d,J=8.2 Hz, 2H), 7.08 (dd, J=2.3, 8.6 Hz, 1H), 7.03 (d, J=2.7 Hz, 1H),6.94 (s, 1H), 5.52 (s, 2H), 4.54 (m, 1H), 2.81 (q, J=7.4 Hz, 2H), 2.50(s, 3H), 2.48 (hidden, 3H), 1.92 (m, 2H), 1.66 (m, 2H), 1.49 (m, 2H),1.44-1.32 (m, 4H), 1.24 (t, J=7.4 Hz, 1H).

Example 209:3-((5′-(Cyclohexyloxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared from5-(cyclohexyloxy)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.014 g, 0.030 mmol), according to the procedure described for thepreparation of Example 204, to give3-((5′-(cyclohexyloxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(0.009 g, 58.8% yield) as an off-white solid. LC-MS (Method J): 1.426min, [M+H]⁺=508.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.50 (d, J=8.6 Hz,1H), 7.08 (dd, J=2.3, 8.6 Hz, 1H), 7.02 (m, 4H), 6.94 (d, J=2.3 Hz, 1H),6.93 (s, 1H), 5.42 (s, 2H), 4.49 (m, 1H), 2.74 (q, J=7.4 Hz, 2H), 2.48(hidden, 6H), 1.92 (m, 2H), 1.68 (m, 2H), 1.53-1.32 (m, 6H), 1.21 (t,J=7.4 Hz, 1H).

Example 210:(4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)(phenyl)methanone

Intermediate 210a: 4-Benzoyl-2-bromobenzonitrile

To a vial containing 4-benzoylbenzonitrile (0.181 g, 0.873 mmol;prepared according to the procedure described by L. J. Gooβen and K.Ghosh, Angew. Chem. Int. Ed. 2001, 40, 3458), NBS (0.171 g, 0.961 mmol),p-toluenesulfonic acid monohydrate (0.083 g, 0.437 mmol) and palladium(II) acetate (0.020 g, 0.087 mmol), was added DCE (10 mL). The vial wasbriefly purged with N₂ and then it was sealed and the mixture wasstirred at 80° C. (block temperature) overnight. The cooled mixture wasevaporated and the residue was taken up in a minimum volume of DCM andthen adsorbed on a silica gel pre-column. Flash chromatography(ISCO/0-50% EtOAc-hexane) gave 4-benzoyl-2-bromobenzonitrile (0.138 g,55.2% yield) as a white crystalline solid. LC-MS (Method J): 1.272 min,+=no ion observed; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.11 (d, J=7.8 Hz,1H), 8.09 (d, J=1.2 Hz, 1H), 7.81 (dd, J=1.6, 7.8 Hz, 1H), 7.76 (d,J=7.4 Hz, 2H), 7.72 (t, J=7.4 Hz, 1H), 7.58 (t, J=7.6 Hz, 2H).

Intermediate 210b:5-Benzoyl-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

A mixture of2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(0.079 g, 0.202 mmol) and 4-benzoyl-2-bromobenzonitrile (0.072 g, 0.253mmol) was reacted according to the method described for the preparationof Intermediate 204b. This afforded5-benzoyl-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.077 g, 81% yield) as a foam which was used as such in the next step.LC-MS (Method J): 1.409 min, [M+H]⁺=471.1; ¹H NMR (400 MHz, CDCl₃) δ ppm7.85-7.90 (m, 2H), 7.78-7.83 (m, 3H), 7.62-7.72 (m, 2H), 7.45-7.57 (m,6H), 6.91 (s, 1H), 5.54 (s, 2H), 2.78-2.88 (m, 2H), 2.65 (s, 3H),)2.59-2.62 (m, 3H), 1.35 (t, J=7.6 Hz, 3H).

Example 210:(4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)(phenyl)methanone

The title compound was prepared from5-benzoyl-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.031 g, 0.065 mmol), according to the procedure described for thepreparation of Example 204, to give(4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)(phenyl)-methanone(0.022 g, 62% yield) as a white solid. LC-MS (Method J): 1.366 min,[M+H]⁺=514.2; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.19 (d, J=7.8 Hz, 1H), 7.90(dd, J=8.2, 1.6 Hz, 1H), 7.81-7.87 (m, 3H), 7.60-7.67 (m, 1H), 7.49-7.55(m, 2H), 7.18 (m, J=8.2 Hz, 2H), 7.08 (m, J=8.2 Hz, 2H), 6.91 (s, 1H),5.46 (s, 2H), 2.70 (q, J=7.4 Hz, 2H), 2.57 (s, 3H), 2.51 (s, 3H), 1.20(t, J=7.6 Hz, 3H).

Example 211:2-Ethyl-5,7-dimethyl-3-((3′-methyl-5′-phenoxy-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 211a:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-3-methyl-[1,1′-biphenyl]-2-carbonitrile

The title compound was prepared from2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(0.300 g, 0.767 mmol) and 2-bromo-4-fluoro-6-methylbenzonitrile (0.180g, 0.843 mmol), according to the method described for the synthesis ofIntermediate 205a, to give4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-3-methyl-[1,1′-biphenyl]-2-carbonitrile(0.220 g, 72.0% yield) as a colourless gum. This material waslyophilized from ACN-H₂O to give a white solid which was used as such inthe next step. LC-MS (Method J): 1.435 min, [M+H]⁺=399.2; ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.52 (d, J=8.2 Hz, 2H), 7.39 (dd, J=2.3, 9.4 Hz,1H), 7.28 (dd, J=2.3, 9.4 Hz, 1H), 7.23 (d, J=8.2 Hz, 2H), 6.94 (s, 1H),5.53 (s, 2H), 2.79 (q, J=7.4 Hz, 2H), 2.53 (s, 3H), 2.50 (s, 3H), 2.49(s, 3H), 1.23 (t, J=7.4 Hz, 3H).

Intermediate 211b:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-methyl-5-phenoxy-[1,1′-biphenyl]-2-carbonitrile

The title compound was prepared from4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-3-methyl-[1,1′-biphenyl]-2-carbonitrile(0.030 g, 0.075 mmol) and phenol (7.79 mg, 0.083 mmol), according to themethod described for the synthesis of Intermediate 205b, to give4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-methyl-5-phenoxy-[1,1′-biphenyl]-2-carbonitrile(0.031 g, 87% yield) as a colourless gum. This material was lyophilizedfrom ACN-H₂O to give a white solid which was used as such in the nextstep.

LC-MS (Method J): 1.571 min, [M+H]⁺=473.2; ¹H NMR (400 MHz, DMSO-d₆) δppm 7.46 (d, J=8.2 Hz, 2H), 7.44 (m, 2H), 7.25 (d, J=7.4 Hz, 1H), 7.20(d, J=8.2 Hz, 2H), 7.14 (dd, J=1.2, 8.6 Hz, 2H), 6.99 (d, J=2.0 Hz, 1H),6.94 (s, 1H), 6.85 (d, J=2.3 Hz, 1H), 5.50 (s, 2H), 2.78 (q, J=7.4 Hz,2H), 2.48 (hidden, 9H), 1.22 (t, J=7.4 Hz, 3H).

Example 211:2-Ethyl-5,7-dimethyl-3-((3′-methyl-5′-phenoxy-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

The title compound was prepared from4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-methyl-5-phenoxy-[1,1′-biphenyl]-2-carbonitrile(0.016 g, 0.034 mmol), according to the procedure described for thepreparation of Example 204, to give2-ethyl-5,7-dimethyl-3-43′-methyl-5′-phenoxy-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine(0.012 g, 68.7% yield) as a white solid. LC-MS (Method J): 1.398 min,[M+H]⁺=516.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.42 (dd, J=7.8, 8.6 Hz,2H), 7.18 (t, J=7.2 Hz, 1H), 7.12 (d, J=7.4 Hz, 2H), 7.01 (d, J=2.3 Hz,1H), 6.93 (s, 3H), 6.91 (s, 1H), 6.84 (d, J=2.3 Hz, 1H), 5.36 (s, 2H),2.67 (q, J=7.4 Hz, 2H), 2.48 (hidden, 3H), 2.47 (s, 3H), 2.00 (s, 3H),1.14 (t, J=7.4 Hz, 3H).

Example 212:3-((5′-(Benzyloxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 212a: 4-(Benzyloxy)-2-bromobenzonitrile

To a solution of benzyl alcohol (0.228 mL, 2.200 mmol) in dry DMF (10mL) was added 60% sodium hydride (0.096 g, 2.400 mmol) and the resultingmixture was stirred at RT under N₂ for 30 min. To the resulting clearsolution was added 2-bromo-4-fluorobenzonitrile (0.400 g, 2.000 mmol)all at once and stirring was continued at RT for 3 h. The reactionmixture was then quenched with saturated aqueous NH₄Cl (2 mL) and thenit was poured into ice-saturated aqueous NH₄Cl and extracted with EtOAc(×2). The combined organic phase was washed (H₂O, brine), dried (Na₂SO₄)and evaporated to give the crude product as an oil which solidified onstanding in vacuo. This material was purified by flash chromatography(ISCO/0-50% EtOAc-hexane) to give 4-(benzyloxy)-2-bromobenzonitrile(0.394 g, 68.4% yield) as an off-white crystalline solid which was usedas such in the next step. LC-MS (Method J): 1.349 min, [M+H]⁺=no ionobserved; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.85 (d, J=8.6 Hz, 1H), 7.54(d, J=2.3 Hz, 1H), 7.45-7.32 (m, 5H), 7.19 (dd, J=2.3, 8.6 Hz, 1H), 5.22(s, 2H).

Intermediate 212b:5-(Benzyloxy)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

A mixture of2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(0.056 g, 0.143 mmol) and 4-(benzyloxy)-2-bromobenzonitrile (0.049 g,0.172 mmol) was reacted according to the method described for thepreparation of Intermediate 204b. This afforded5-(benzyloxy)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.031 g, 45.8% yield) as a colourless gum which was used as such in thenext step. LC-MS (Method J): 1.502 min, [M+H]⁺=473.2; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.83 (d, J=9.0 Hz, 1H), 7.52 (d, J=8.2 Hz, 2H), 7.43 (d,J=7.0 Hz, 2H), 7.38 (t, J=7.2 Hz, 2H), 7.35-7.30 (m, 1H), 7.23 (d, J=8.6Hz, 2H), 7.17 (s, 1H), 7.15 (m, 1H), 6.94 (s, 1H), 5.52 (s, 2H), 5.22(s, 2H), 2.80 (q, J=7.4 Hz, 2H), 2.50 (s, 3H), 2.48 (hidden, 3H), 1.24(t, J=7.4 Hz, 3H).

Example 212:3-((5′-(Benzyloxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared from5-(benzyloxy)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.013 g, 0.028 mmol), according to the procedure described for thepreparation of Example 204, to give3-((5′-(benzyloxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(0.014 g, 99% yield) as a white solid. LC-MS (Method J): 1.365 min,[M+H]⁺=516.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.54 (d, J=8.6 Hz, 1H),7.45 (d, J=7.0 Hz, 2H), 7.38 (t, J=7.0 Hz, 2H), 7.32 (m, 1H), 7.16 (dd,J=2.3, 8.2 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 7.02 (s, 4H), 6.93 (s, 1H),5.42 (s, 2H), 5.21 (s, 2H), 2.74 (q, J=7.4 Hz, 2H), 2.48 (hidden, 6H),1.20 (t, J=7.4 Hz, 3H).

Example 213:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carboxylicacid

Intermediate 213a: Methyl 2-bromo-4-phenoxybenzoate

To a solution of phenol (0.207 g, 2.200 mmol) in dry DMF (10 mL) wasadded 60% sodium hydride (0.096 g, 2.400 mmol) and the resulting mixturewas stirred at RT under N₂ for 30 min. To the resulting clear solutionwas added methyl 2-bromo-4-fluorobenzoate (0.476 g, 2.000 mmol) all atonce and stirring was continued at RT for 18 h. The reaction mixture wasquenched with saturated aqueous NH₄Cl (2 mL) and then it was poured intoice H₂O and extracted with EtOAc (×2). The combined organic phase wasdried (Na₂SO₄) and evaporated to give a colourless oil. This oil waspurified by flash chromatography (ISCO/0-30% EtOAc-hexane) to givemethyl 2-bromo-4-phenoxybenzoate (0.358 g, 58.3% yield) as a colourlessoil which was used as such in the next step. LC-MS (Method J): 1.391min, [M+H]⁺=307.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.83 (d, J=8.6 Hz,1H), 7.46 (dd, J=7.4, 8.6 Hz, 2H), 7.26 (m, 2H), 7.15 (dd, J=1.2, 9.0Hz, 2H), 7.02 (dd, J=2.3, 8.6 Hz, 1H), 3.81 (s, 3H).

Intermediate 213b: Methyl4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carboxylate

A mixture of2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(001d, 0.060 g, 0.153 mmol), methyl 2-bromo-4-phenoxybenzoate (0.059 g,0.192 mmol) and 2 M Na₂CO₃ (0.230 mL, 0.460 mmol) in toluene-methanol(9:1, 5 mL) was purged with a stream of N₂ for 5 min in a sealable vial.To this mixture was added Pd (Ph₃P)₄ (0.018 g, 0.015 mmol), the vial wassealed and the mixture was stirred at 95° C. (block temperature) for 16h. The cooled mixture was diluted with EtOAc and the organic phase wasseparated, dried (Na₂SO₄) and evaporated to give a gum. This materialwas purified by flash chromatography (ISCO/0-100% EtOAc-DCM) to give theimpure product as a colourless gum.

This gum was repurified by preparative LC (Method D) to give methyl4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carboxylate(0.020 g, 26.5% yield) as a gum. This gum was lyophilized from ACN-H₂Oto give a white solid which was used as such in the next step. LC-MS(Method J): 1.563 min, [M+H]⁺=492.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.77 (d, J=8.6 Hz, 1H), 7.42 (dd, J=7.4, 8.2 Hz, 2H), 7.21 (d, J=8.6 Hz,1H), 7.19 (d, J=8.2 Hz, 2H), 7.11 (t, J=8.2 Hz, 4H), 6.98 (dd, J=2.7,8.6 Hz, 1H), 6.94 (s, 1H), 6.87 (d, J=2.3 Hz, 1H), 5.47 (s, 2H), 3.52(s, 3H), 2.76 (q, J=7.4 Hz, 2H), 2.48 (hidden, 6H), 1.21 (t, J=7.4 Hz,3H).

Example 213:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carboxylicacid

To a solution of methyl4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy[1,1′-biphenyl]-2-carboxylate(0.010 g, 0.020 mmol) in THF (2 mL) was added a solution of LiOHmonohydrate (1.742 mg, 0.041 mmol) in H₂O (1 mL) and the resultingsolution was stirred at RT for 18 h and then it was heated at 80° C. ina sealed vial for 2 days. The volatiles were then removed in vacuo, theresidue was taken up in DMF (1.8 mL, acidified with 10 drops of AcOH)and the mixture was submitted to preparative LC purification (Method D).The product-containing fractions were combined and evaporated to give4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carboxylicacid (0.005 g, 51.5% yield) as a white solid. LC-MS (Method J): 1.408min, [M+H]⁺=478.1; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.56 (br s, 1H),7.76 (d, J=8.6 Hz, 1H), 7.41 (dd, J=7.4, 8.6 Hz, 2H), 7.22 (d, J=8.6 Hz,2H), 7.18 (d, J=7.4 Hz, 2H), 7.10 (t, J=8.2 Hz, 4H), 6.95 (dd, J=2.3,8.6 Hz, 1H), 6.93 (s, 1H), 6.82 (d, J=2.3 Hz, 1H), 5.46 (s, 2H), 2.76(q, J=7.4 Hz, 2H), 2.48 (hidden, 6H), 1.22 (t, J=7.4 Hz, 3H).

Example 214:3-(4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-[1,1′-biphenyl]-2-yl)-1,2,4-oxadiazol-5(4H)-one

Intermediate 214a:(Z)-4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-N′-hydroxy-[1,1′-biphenyl]-2-carboximidamide

To a sealable vial was added4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-[1,1′-biphenyl]-2-carbonitrile(205b, 0.042 g, 0.088 mmol), 1-butyl-3-methylimidazolium acetate (1.00g, 5.04 mmol) and hydroxylamine hydrochloride (0.153 g, 2.203 mmol). Thevial was sealed and the mixture were stirred at 50° C. (blocktemperature) for

16 h. The cooled mixture was diluted with DMF (1 mL) and then H₂O (0.5mL) was added. The solution was acidified by the dropwise addition ofTFA (0.5 mL) and the volume was adjusted with DMF to give 2×1.8 mLsamples that were submitted to preparative LC purification (Method D).The product-containing fractions were combined and evaporated to give(Z)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-N′-hydroxy-[1,1′-biphenyl]-2-carboximidamide(0.032 g, 71.3% yield) as a gum. This material was used as such in thenext step. LC-MS (Method J): 1.227 min, [M+H]⁺=510.2.

Example 214:3-(4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-[1,1′-biphenyl]-2-yl)-1,2,4-oxadiazol-5(4H)-one

To a sealable vial was added(Z)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-N′-hydroxy-[1,1′-biphenyl]-2-carboximidamide(0.032 g, 0.063 mmol), N,N′-carbonyldiimidazole (0.072 g, 0.445 mmol),DBU (0.067 mL, 0.445 mmol) and dry THF (3 mL). The vial was then sealedand the mixture was stirred at 50° C. (block temperature) for 2 h. Thecooled mixture was evaporated and the residue was taken up in DMF (2×1.8mL, acidified with 20 drops of AcOH) and submitted to preparative LCpurification (Method D). The product-containing fractions were combinedand evaporated to give3-(4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2-fluorophenoxy)-[1,1′-biphenyl]-2-yl)-1,2,4-oxadiazol-5(4H)-one(0.023 g, 48.3% yield) as a white solid. LC-MS (Method J): 1.391 min,+536.3; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.29 (br s, 1H), 7.62 (d, J=8.2Hz, 1H), 7.42 (m, 1H), 7.36-7.29 (m, 2H), 7.27 (dd, J=2.0, 7.4 Hz, 1H),7.23 (d, J=8.2 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H), 7.03 (dd, J=2.7, 8.2 Hz,1H), 7.01 (m, 1H), 6.93 (s, 1H), 5.47 (s, 2H), 2.75 (q, J=7.4 Hz, 2H),2.48 (hidden, 6H), 1.19 (t, J=7.4 Hz, 3H).

Example 215:3-((5′-(1H-Indazol-1-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 215a and 215b: 2-Bromo-4-(1H-indazol-1-yl)benzonitrile and2-Bromo-4-(2H-indazol-2-yl)benzonitrile

A mixture of 2-bromo-4-fluorobenzonitrile (0.200 g, 1.000 mmol),1H-indazole (0.130 g, 1.100 mmol) and potassium carbonate (0.276 g,2.000 mmol) in dry DMF (5 mL) was stirred at 120° C. (block temperature)in a sealed vial for 16 h. The cooled mixture was filtered through asmall plug of cotton wool to remove the potassium salts and the residuewas washed with a little DMF. The filtrate was evaporated to give aturbid orange gum which was purified by flash chromatography(ISCO/50-100% DCM-hexane) to give2-bromo-4-(1H-indazol-1-yl)benzonitrile (Intermediate 215a, 0.179 g,60.0% yield) as a white solid. LC-MS (Method J): 1.402 min,[M+H]⁺=297.9, 299.9; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.53 (s, 1H), 8.28(d, J=2.0 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.07 (dd, J=2.0, 8.6 Hz, 1H),8.03 (d, J=8.6 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.59 (dd, J=7.4, 8.2 Hz,1H), 7.35 (t, J=7.4 Hz, 1H). Further elution afforded2-bromo-4-(2H-indazol-2-yl)benzonitrile (Intermediate 215b, 0.078 g,26.2% yield) as a white solid. LC-MS (Method J): 1.385 min,[M+H]⁺=298.0, 300.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.32 (s, 1H), 8.64(d, J=2.0 Hz, 1H), 8.33 (dd, J=2.0, 8.6 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H),7.76 (d, J=8.6 Hz, 1H), 7.70 (d, J=9.0 Hz, 1H), 7.35 (dd, J=6.7, 7.8 Hz,1H), 7.12 (dd, J=6.7, 8.2 Hz, 2H).

Intermediate 215c:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(1H-indazol-1-yl)-[1,1′-biphenyl]-2-carbonitrile

A mixture of2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(001d, 0.100 g, 0.256 mmol), 2-bromo-4-(1H-indazol-1-yl)benzonitrile(215a, 0.084 g, 0.281 mmol) and 2 M Na₂CO₃ (0.319 mL, 0.639 mmol) intoluene-ethanol (9:1, 5 mL) was purged with a stream of N₂ for 5 min ina sealable vial. To this mixture was added Pd (Ph₃P)₄ (0.030 g, 0.026mmol), the vial was sealed and the mixture was stirred at 95° C. (blocktemperature) for 16 h. The cooled mixture was diluted with EtOAc and theorganic phase was separated, dried (Na₂SO₄) and evaporated to give apale yellow gum. This material was purified by flash chromatography(ISCO/0-100% EtOAc-DCM) to give4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(1H-indazol-1-yl)-[1,1′-biphenyl]-2-carbonitrile(0.106 g, 86% yield) as a colourless gum which solidified on standing invacuo to give a waxy solid. This material was used as such in the nextstep. LC-MS (Method J): 1.396 min, [M+H]⁺=483.2; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.49 (s, 1H), 8.12 (d, J=8.2 Hz, 1H), 8.20 (d, J=8.2 Hz,2H), 7.95 (d, J=2.3 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.66 (d, J=7.8 Hz,2H), 7.60 (dd, J=6.7, 11.7 Hz, 2H), 7.54 (m, 2H), 7.32 (t, J=7.8 Hz,1H), 7.28 (d, J=7.8 Hz, 2H), 6.95 (s, 1H), 5.55 (s, 2H), 2.82 (q, J=7.4Hz, 2H), 2.51 (s, 3H), 2.50 (s, 3H), 1.25 (t, J=7.4 Hz, 3H).

Example 215:3-((5′-(1H-Indazol-1-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a sealable vial containing4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(1H-indazol-1-yl)-[1,1′-biphenyl]-2-carbonitrile(0.025 g, 0.052 mmol) and dibutyltin oxide (0.026 g, 0.104 mmol) intoluene (2 mL) was added TMS-N₃ (0.138 mL, 1.036 mmol). The vial wassealed and the mixture were stirred at 120° C. (block temperature) for16 h. The cooled mixture was evaporated and the residue was taken up inDMF (1.8 mL, acidified with 15 drops of AcOH) and submitted topreparative LC purification (Method D). The product-containing fractionswere combined and evaporated to give3-((5′-(1H-indazol-1-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(0.020 g, 73.5% yield) as a white solid. LC-MS (Method J): 1.342 min,[M+H]⁺=526.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.44 (s, 1H), 7.98 (d,J=8.6 Hz, 2H), 7.91 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.83 (brs, 1H), 7.53 (dd, J=7.4, 8.2 Hz, 1H), 7.30 (dd, J=7.0, 7.8 Hz, 1H), 7.17(d, J=8.2 Hz, 2H), 7.06 (d, J=8.2 Hz, 2H), 6.93 (s, 1H), 5.45 (s, 2H),2.75 (q, J=7.4 Hz, 2H), 2.48 (hidden, 6H), 1.21 (t, J=7.4 Hz, 3H).

Example 216:3-((5′-(2H-Indazol-2-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 216a:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2H-indazol-2-yl)-[1,1′-biphenyl]-2-carbonitrile

The title compound was prepared from2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(001d, 0.080 g, 0.204 mmol) and 2-bromo-4-(2H-indazol-2-yl)benzonitrile(215b, 0.067 g, 0.225 mmol), according to the method described for thepreparation of Intermediate 215c to give4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2H-indazol-2-yl)-[1,1′-biphenyl]-2-carbonitrile(0.066 g, 66.9% yield) as a colourless gum which solidified on standingin vacuo to give a waxy solid. This material was used as such in thenext step. LC-MS (Method J): 1.375 min, [M+H]⁺=483.1; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 9.34 (s, 1H), 8.31 (s, 1H), 8.29 (dd, J=2.0, 6.7 Hz, 1H),8.15 (d, J=9.0 Hz, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.68 (t, J=8.8 Hz, 2H),7.63-7.51 (m, 2H), 7.33 (dd, J=6.3 Hz, 1H), 7.30 (d, J=8.2 Hz, 2H), 7.11(dd, J=7.0, 8.6 Hz, 1H), 6.96 (s, 1H), 5.56 (s, 2H), 2.83 (q, J=7.4 Hz,2H), 2.51 (s, 3H), 2.50 (s, 3H), 1.26 (t, J=7.4 Hz, 3H).

Example 216:3-((5′-(2H-Indazol-2-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

The title compound was prepared from4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(2H-indazol-2-yl)-[1,1′-biphenyl]-2-carbonitrile(0.025 g, 0.052 mmol), according to the method described for thepreparation of Example 215 to give3-((5′-(2H-indazol-2-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(0.019 g, 69.8% yield) as a pale yellow solid. LC-MS (Method J): 1.318min, [M+H]⁺=526.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 9.28 (s, 1H), 8.24(dd, J=2.0, 8.2 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H),7.75 (d, J=8.6 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.52 (dd, J=6.7, 9.0 Hz,1H), 7.17 (d, J=8.2 Hz, 2H), 7.11 (d, J=8.6 Hz, 1H), 7.07 (d, J=8.2 Hz,2H), 6.94 (s, 1H), 5.46 (s, 2H), 2.77 (q, J=7.4 Hz, 2H), 2.48 (hidden,6H), 1.23 (t, J=7.4 Hz, 3H).

Example 217:2-Ethyl-5,7-dimethyl-3-((5′-(4-methyl-1H-pyrazol-1-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 217a:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(4-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-2-carbonitrile

To a solution of4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile(205a, 0.088 g, 0.229 mmol) and 4-methyl-1H-pyrazole (0.028 g, 0.343mmol) in DMF (3 mL) was added potassium carbonate (0.095 g, 0.687 mmol)and the resulting mixture was stirred at 120° C. (block temperature) ina sealed vial for 18 h. The cooled mixture was filtered (0.45 μm syringefilter) to remove the potassium salts and the residue was washed with alittle DMF. The combined filtrate was evaporated to give a gum which waspurified by flash chromatography (ISCO/0-100% EtOAc-DCM) to give4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(4-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-2-carbonitrile(0.102 g, 100% yield) as a colourless gum which solidified on standingin vacuo to give a white solid. This material was used as such in thenext step. LC-MS (Method J): 1.340 min, [M+H]⁺=447.2; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.50 (s, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.96 (d, J=7.8 Hz,1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.2Hz, 2H), 6.95 (s, 1H), 5.55 (s, 2H), 2.81 (q, J=7.4 Hz, 2H), 2.51 (s,3H), 2.50 (s, 3H), 2.07 (s, 3H), 1.25 (t, J=7.4 Hz, 3H).

Example 217:2-Ethyl-5,7-dimethyl-3-((5′-(4-methyl-1H-pyrazol-1-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a sealable vial containing4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(4-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-2-carbonitrile(0.100 g, 0.224 mmol) and dibutyltin oxide (0.084 g, 0.336 mmol) intoluene (4 mL) was added TMS-N₃ (0.297 mL, 2.239 mmol). The vial wassealed and the mixture were stirred at 120° C. (block temperature) for16 h. The cooled mixture was evaporated and the residue was taken up inDMF (4×1.8 mL, acidified with 20 drops of AcOH) and submitted topreparative LC purification (Method D). The product-containing fractionswere combined and evaporated to give a gum which was lyophilized fromACN-H₂O to give2-ethyl-5,7-dimethyl-3-((5′-(4-methyl-1H-pyrazol-1-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine(0.062 g, 56.6% yield) as a white solid. LC-MS (Method J): 1.515 min,[M+H]⁺=490.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.41 (s, 1H), 7.87 (d,J=8.6 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.58 (s, 1H), 7.10(d, J=8.2 Hz, 2H), 7.01 (d, J=8.2 Hz, 2H), 6.93 (s, 1H), 5.43 (s, 2H),2.76 (q, J=7.4 Hz, 2H), 2.48 (hidden, 6H), 2.08 (s, 3H), 1.22 (t, J=7.4Hz, 3H).

The following examples have been similarly prepared from4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile(Intermediate 205a) as described above for Example 217. Two analyticalLC injections were used to determine the final purity; the retentiontime of one of them is reported for each compound and is referred asMethod J.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 218

489.75 490.1; 1.479 min (Method J) 8.54 (d, J = 2.3 Hz, 1H), 7.94 (dd, J= 2.0, 8.2 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H),7.11 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 6.93 (s, 1H), 6.36(d, J = 2.3 Hz, 1H), 5.45 (s, 2H), 2.75 (q, J = 7.4 Hz, 2H), 2.48(hidden, 6H), 2.26 (s, 3H), 1.22 (t, J = 7.4 Hz, 3H). 219

543.55 544.2; 1.520 min (Method J) 8.89 (s, 1H), 8.02 (d, J = 8.2 Hz,1H), 7.93 (s, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 8.2 Hz, 2H),7.08 (d, J = 2.7 Hz, 1H), 7.05 (d, J = 8.2 Hz, 2H), 6.93 (s, 1H), 5.45(s, 2H), 2.76 (q, J = 7.4 Hz, 2H), 2.48 (hidden, 6H), 1.23 (t, J = 7.4Hz, 3H). 220

489.57 490.1; 1.110 min (Method J) (MeOH-d₄): 8.57 (br s, 1H), 8.15 (brs, 1H), 7.97 (s, 1H), 7.83 (br s, 1H), 7.61 (s, 2H), 7.13 (d, J = 7.0Hz, 2H), 7.06 (d, J = 7.4 Hz, 2H), 7.01 (s, 1H), 5.53 (s, 2H), 2.84 (q,J = 7.8 Hz, 2H), 2.59 (s, 3H), 2.56 (s, 3H), 2.31 (br s, 3H), 1.25 (t, J= 7.4 Hz, 3H). 221

489.57 490.1; 1.153 min (Method J) (MeOH-d₄): 8.64 (s, 1H), 8.10 (s,1H), 7.78 (d, J = 9.0 Hz, 1H), 7.72-7.71 (m, 2H), 7.59 (s, 1H), 7.14 (d,J = 8.2 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 7.02 (s, 1H), 5.54 (s, 2H),2.85 (q, J = 7.8 Hz, 2H), 2.59 (s, 3H), 2.56 (s, 3H), 2.31 (s, 3H), 1.25(t, J= 7.4 Hz, 3H). 222

525.61 526.2; 1.473 min (Method J) 8.69 (s, 1H), 7.84 (m, 2H), 7.85 (d,J = 2.0 Hz, 1H), 7.76 (dd, J = 7.0, 8.6 Hz, 1H), 7.72 (m, 1H), 7.33 (m,1H), 7.17 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 7.8 Hz, 2H), 6.92 (s, 1H),5.44 (s, 2H), 2.75 (q, J = 7.4 Hz, 2H), 2.48 (hidden, 6H), 1.22 (t, J =7.4 Hz, 3H). 223

503.60 504.1; 1.329 min (Method J) 8.35 (s, 1H), 7.88 (dd, J = 2.0, 8.2Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.10 (d, J= 7.8 Hz, 2H), 7.05 (d, J = 8.2 Hz, 2H), 6.93 (s, 1H), 5.45 (s, 2H),2.75 (q, J = 7.4 Hz, 2H), 2.48 (hidden, 6H), 2.17 (s, 3H), 2.00 (s, 3H),1.22 (t, J = 7.4 Hz, 3H). 224

543.55 544.1; 1.317 min (Method J) 9.37 (s, 1H), 8.26 (s, 1H), 8.05 (d,J = 8.2 Hz, 1H), 8.00 (s, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.13 (d, J =8.2 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 6.93 (s, 1H), 5.45 (s, 2H), 2.76(q, J = 7.4 Hz, 2H), 2.48 (hidden, 6H), 1.22 (t, J = 7.4 Hz, 3H).

Example 225:3-((5′-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-2′-(5H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 225a:5-Amino-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

To a mixture of 4-amino-2-bromobenzonitrile (1.00 g, 5.08 mmol),2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(001d, 1.773 g, 4.53 mmol) and K₂CO₃ (2.505 g, 18.13 mmol) was added1,4-dioxane and H₂O (2:1, 30 mL). The reaction mixture was then purgedwith a stream of N₂ for 5 min in a sealable vial before Pd (Ph₃P)₄(0.262 g, 0.227 mmol) was added. The reaction vial was sealed and themixture heated at 100° C. for 18 h. The cooled reaction mixture was thendiluted with EtOAc (50 mL), washed with H₂O and brine, dried (Na₂SO₄)and evaporated. The crude residue was purified by flash chromatography(ISCO, 0-100% EtOAc-DCM) to afford the title compound (1.46 g, 4.53mmol, 85%) as a white solid. LC-MS (Method H): 1.220 min, [M+H]⁺=382.5;¹H NMR (400 MHz, CDCl₃) δ ppm 7.37-7.55 (m, 3H), 7.19 (d, J=8.2 Hz, 2H),6.90 (s, 1H), 6.51-6.68 (m, 2H), 5.51 (s, 2H), 4.17 (br s, 2H), 2.81 (d,J=7.4 Hz, 2H), 2.59 (s, 3H), 2.64 (s, 3H), 1.33 (t, J=7.4 Hz, 3H).

Intermediate 225b:5-Azido-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

To a solution of5-amino-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.500 g, 1.311 mmol) in ACN (40 mL) was added TFA (0.202 mL, 2.622mmol) and the mixture was cooled at −5° C. To this cold mixture wasadded tert-butyl nitrite (0.624 mL, 5.240 mmol), followed after 10 minwith TMS-N₃ (0.522 mL, 3.930 mmol). The mixture was then stirred at RTfor 4 h, after which it was evaporated to dryness. The crude residueobtained was purified by flash chromatography (ISCO, 0-100% EtOAc-DCM)to provide5-azido-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.467 g, 1.088 mmol, 83% yield). LC-MS (Method H): 1.335 min,[M+H]⁺=408.5; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.88 (d, J=8.2 Hz, 1H),7.51 (d, J=8.2 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.16-7.26 (m, 2H), 7.08(s, 1H), 5.59 (s, 2H), 2.93 (q, J=7.2 Hz, 2H), 2.49 (s, 6H), 1.21 (t,J=7.4 Hz, 3H).

Intermediate 225c:5-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

To a mixture of5-azido-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.030 g, 0.074 mmol) and ethynylcyclopropane (0.049 g, 0.736 mmol) in amixture of t-BuOH:H₂O (3:1, 4 mL) were added CuSO₄.5H₂O (0.002 g, 0.008mmol) and sodium ascorbate (0.007 g, 0.040 mmol). The reaction mixturewas stirred for at RT for 16 h and then it was diluted with EtOAc (25mL) and washed with saturated aqueous NH₄Cl and H₂O. The organic layerwas separated, dried (Na₂SO₄) and evaporated to dryness. The crudeproduct thus obtained was washed with hexane (5 mL) to remove excessalkyne and dried in vacuo to afford the title compound (0.025 g, 0.074mmol, 64.8%) which was used as such for the next step without furtherpurification. LC-MS (Method H): 1.313 min, [M+H]⁺=474.2.

Example 225:3-((5′-(4-Cyclopropyl-1H-1,2,3-triazol-1-yl)-2′-(5H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a mixture of5-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.025 g, 0.053 mmol), TMS-N₃ (0.148 mL, 1.056 mmol) and dibutyltinoxide (0.027 g, 0.106 mmol) was added toluene (2 mL), the vial wasbriefly purged with N₂ and then it was sealed. The mixture was stirredat 120° C. for 16 h and then the cooled mixture was filtered through asmall plug of cotton wool and the filtrate was evaporated to give a gum.This gum was purified by preparative LC (Method F) to afford3-((5′-(4-cyclopropyl-1H-1,2,3-triazol-1-yl)-2′-(5H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine(0.015 g, 0.053 mmol, 52.3% yield) as a white solid. LC-MS (Method H) at1.259 min, [M+H]⁺=517.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.70 (s, 1H),8.03 (d, J=8.2 Hz, 1H), 7.91 (s, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.11-7.19(m, J=7.8 Hz, 2H), 7.01-7.11 (m, J=8.2 Hz, 2H), 6.95 (s, 1H), 5.47 (s,2H), 2.78 (q, J=7.4 Hz, 3H), 2.48 (hidden, 6H), 1.96-2.08 (m, 1H),1.18-1.31 (m, 3H), 0.91-1.02 (m, 2H), 0.71-0.82 (m, 2H).

The following examples have been similarly prepared from5-azido-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(Intermediate 225b) as described for the synthesis of Example 225 above.Two analytical LC-MS injections were used to determine the final purity.The retention time of one of them is reported for each compound and isreferred as Method H.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW (MethodH) δ ppm 226

520.5 521.2; 1.18 min 8.74 (s, 1H), 8.03 (dd, J = 1.96, 8.22 Hz, 1H),7.92 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.10-7.19 (d, J =8.2 Hz, 2H), 7.02-7.08 (d, J = 8.2 Hz, 2H), 6.95 (s, 1H), 6.53 (s, 1H),5.46 (s, 2H), 4.76 (m, 1H), 3.64- 3.73 (m, 2H), 2.86 (t, J = 6.85 Hz,2H), 2.78 (q, J = 7.70 Hz, 2H), 2.48 (hidden, 6H), 1.25 (t, J = 7.43 Hz,3H). 227

518.6 519.2; 1.283 min 8.73 (s, 1H), 7.99 (d, J = 7.04 Hz, 1H), 7.87 (brs, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.11-7.22 (d, J = 7.8 Hz, 2H),6.99-7.08 (d, J = 8.2 Hz, 2H), 6.94 (s, 1H), 6.53 (s, 1H), 5.45 (s, 2H),3.06 (td, J = 6.8, 13.7 Hz, 1H), 2.78 (q, J = 7.30 Hz, 2H), 2.50(hidden, 6H), 1.30 (d, J = 7.04 Hz, 6H), 1.25 (t, J = 7.4 Hz, 3H). 228

518.6 519.2; 1.294 min 8.73 (s, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.91 (d,J = 1.6 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.09-7.18 (d, J = 8.2 Hz,2H), 7.00-7.08 (d, J = 7.8 Hz, 2H), 6.93 (s, 1H), 6.50 (s, 1H), 5.44 (s,2H), 2.76 (q, J = 7.4 Hz, 2H), 2.63-2.70 (m, 2H), 2.50 (hidden, 6H),1.61-1.71 (m, 2H), 1.22 (t, J = 7.6 Hz, 4H), 0.94 (t, J = 7.4 Hz, 3H).229

542.6 543.2; 1.356 min 8.95 (s, 1H), 8.24 (br s, 1H), 7.92 (dd, J = 2.4,7.8 Hz, 2H), 7.76-7.83 (m, 2H), 7.12-7.20 (d, J = 7.8 Hz, 2H), 6.99-7.04(d, J = 8.22 Hz, 2H), 6.94 (s, 1H), 6.53 (br s, 1H), 6.32 (t, J = 2.15Hz, 1H), 5.45 (s, 2H), 2.80 (q, J = 7.4 Hz, 3H), 2.50 (hidden, 6H),2.65-2.72 (m, 2H), 1.93-2.02 (m, 2H), 1.24-1.31 (m, 5H). 230

544.2 545.2; 1.344 min (MeOH-d₄) 8.49 (s, 1H), 7.95-8.08 (m, 2H), 7.85(d, J = 8.6 Hz, 1H), 7.16-7.24 (d, J = 8.2 Hz, 2H), 7.10- 7.16 d, J =8.2 Hz, 2H), 7.05 (s, 1H), 5.58 (s, 2H), 2.88 (q, J = 7.7 Hz, 2H), 2.59(s, 3H), 2.62 (s, 3H), 2.09- 2.23 (m, 2H), 1.67-1.89 (m, 6H), 1.33 (s,1H), 1.28 (t, J = 7.4 Hz, 3H). 231

504.5 505.5, 1.24 min (MeOH-d₄) 8.45 (s, 1H), 7.97 (s, 2H), 7.15 (d, J =7.8 Hz, 2H), 7.09 (d, J = 7.8 Hz, 2H), 7.03 (s, 1H), 5.55 (s, 2H), 2.85(qd, J = 7.5, 14.9 Hz, 4H), 2.59 (s, 3H), 2.62 (s, 3H), 1.36 (t, J = 7.6Hz, 3H), 1.28 (t, J = 7.6 Hz, 3H) 232

490.5 491.2; 1.396 min (MeOH-d₄) 8.42 (s, 1H), 7.95-8.03 (m, 2H), 7.83(d, J = 8.61 Hz, 1H), 7.15-7.21 (d, J = 8.22 Hz, 2H), 7.07- 7.11 (d, J =8.22 Hz, 2H), 7.04 (s, 1H), 5.57 (s, 2H), 2.87 (q, J = 7.43 Hz, 2H),2.62 (s, 3H), 2.59 (s, 3H), 2.43 (s, 3H), 1.28 (t, J = 7.63 Hz, 3H).

Example 233:1-(4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)-1H-benzo[d][1,2,3]triazole

Intermediate 233a:5-(1H-Benzo[d][1,2,3]triazol-1-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

To a mixture of5-azido-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(Intermediate 225b, 0.030 g, 0.074 mmol) and trimethylsilyl)phenyltrifluoromethanesulfonate (0.088 g, 0.294 mmol) in ACN (4 mL) was addedCsF (0.0122 g, 0.074 mmol) and the mixture was stirred at RT for 7 h.The mixture was then diluted with EtOAc (25 mL) and the organic layerwas washed (saturated aqueous NaHCO₃), dried (Na₂SO₄) and evaporated todryness. This gave crude5-(1H-benzo[d][1,2,3]triazol-1-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.025 g, 0.052 mmol, 70.2% yield) which was used as such for the nextstep. LC-MS (Method H): 1.366 min, [M+H]⁺=484.2.

Example 233:1-(4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)-1H-benzo[d][1,2,3]triazole

To a mixture of5-(1H-benzo[d][1,2,3]triazol-1-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.025 g, 0.052 mmol), TMS-N₃ (0.144 mL, 1.034 mmol) and dibutyltinoxide (0.0263 g, 0.103 mmol) was added toluene (3 mL). The vial wasbriefly purged with N₂ and then it was sealed and the mixture wasstirred at 120° C. for 16 h. The cooled mixture was evaporated to give agum which was purified by preparative LC (Method F) to provide1-(4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-6-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)-1H-benzo[d][1,2,3]triazole(0.010 g, 36.7% yield) as a white solid. HRMS (ESI): Calcd. forC₃₀H₂₈N₇O m/z 527.2415; found 527.2418; ¹H NMR (400 MHz, MeOH-d4) δ ppm8.14 (d, J=8.6 Hz, 1H), 7.83-8.03 (m, 4H), 7.70 (t, J=7.43 Hz, 1H),7.51-7.60 (m, 1H), 7.18-7.26 (d, J=7.8 Hz, 2H), 7.05-7.14 (d, J=7.8 Hz,2H), 7.03 (s, 1H), 5.56 (s, 2H), 2.87 (q, J=7.7 Hz, 2H), 2.61 (s, 3H),2.58 (s, 3H), 1.28 (t, J=7.43 Hz, 3H).

Example 234:2-Ethyl-3-((5′-(1-ethyl-1H-1,2,3-triazol-4-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 234a: 4-Bromo-2-iodobenzonitrile

To a mixture of 2-amino-4-bromobenzonitrile (1.00 g, 5.08 mmol) in 4 Maqueous HCl (7.5 rot) cooled at 0° C. was added a solution of sodiumnitrite (0.490 g, 7.11 mmol) in H₂O (3 mL), followed after 10 min by thedropwise addition of a solution of potassium iodide (2.106 g, 12.69mmol) in H₂O (3 mL). The reaction mixture was subsequently allowed towarm to RT and then it was extracted with EtOAc (50 mL). The organiclayer was separated, washed (10% aqueous Na₂S₂O₅, brine), dried (Na₂SO₄)and evaporated under reduced pressure. The residue obtained was purifiedby flash chromatography (ISCO, 0 to 100% EtOAc-hexane) to provide4-bromo-2-iodobenzonitrile (1.17 g, 3.81 mmol, 75% yield). LC-MS (MethodH): 1.239 min, [M+H]⁺=no ion observed. ¹H NMR (400 MHz, CDCl₃) δ ppm7.46 (d, J=8.22 Hz, 1H), 7.61 (dd, J=8.22 Hz, 1.76 Hz, 1H), 8.10 (d,J=1.96 Hz, 1H).

Intermediate 234b:5-Bromo-4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile

Method A: A mixture of 4-bromo-2-iodobenzonitrile (0.300 g, 0.974 mmol),2-ethyl-5,7-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3H-imidazo[4,5-b]pyridine(001d, 0.419 g, 1.072 mmol) and K₂CO₃ (0.539 g, 3.900 mmol) in1,4-dioxane and H₂O (2:1, 15 mL) was purged with a stream of N₂ for 10min and then Pd (Ph₃P)₄ (0.113 g, 0.097 mmol) was added. The reactionvial was then sealed and the mixture was stirred at 95° C. for 3 h. Thecooled reaction mixture was then diluted with EtOAc (50 mL) and theorganic layer was washed (H₂O, brine), dried (Na₂SO₄) and evaporated todryness. The crude residue obtained was purified by flash chromatography(ISCO/0 to 100% EtOAc-hexane) to give the title compound (0.270 g, 0.650mmol, 89% yield) as a white foam. LC-MS (Method H): 1.354 min,(M+H)=445.5; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.71-7.94 (m, 3H), 7.54 (d,J=8.22 Hz, 2H), 7.24 (d, J=8.2 Hz, 2H), 6.94 (s, 1H), 5.53 (s, 2H) 2.80(q, J=7.43 Hz, 2H), 2.50 (hidden, 6H), 1.23 (t, J=7.43 Hz, 3H).

Method B: To an ice-cold solution of2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (001c, 2.00 g, 11.41mmol) in dry DMF (40 mL) was added NaH (60% in oil, 0.593 g, 14.84mmol). The resulting brown mixture was stirred for 5 min and then thecooling bath was removed and stirring was continued at RT for 1 h. Theresulting brown solution was re-cooled at 0° C. and a solution of5-bromo-4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (I-001, 4.41 g,12.55 mmol) in dry DMF (30 mL) was added dropwise. The reaction mixturewas then stirred at RT for 3 h, before being poured into ice-H₂O (100mL) containing saturated aqueous NH₄Cl (50 mL) and vigorously stirring.This suspension was then extracted with DCM (100 mL) and the organicphase was washed (50% brine), dried (Na₂SO₄) and evaporated to give apale amber gum. This gum was purified by flash chromatography(ISCO/0-100% EtOAc-hexane) to afford5-bromo-4C′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(3.01 g, 59% yield) as a white solid. This material was identical(LC-MS, 41 NMR) with the material prepared by Method A above.

Intermediate 234c:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-2-carbonitrile

In a 50 mL vial was added5-bromo-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(1.00 g, 2.245 mmol) in THF (10 mL) and TEA (20 mL) to give a colorlesssolution. This mixture was degassed with a stream of Na for 5 min andthen [Pd (PPh₃)₂Cl₂] (0.079 g, 0.112 mmol) and copper (I) iodide (0.043g, 0.225 mmol) were added. To this mixture was addedethynyltrimethylsilane (1.598 mL, 11.230 mmol) dropwise and then it wasstirred at 70° C. for 2 h. The reaction mixture was then cooled to RTand the volatiles were removed under reduced pressure. The residue wastaken up in EtOAc (50 mL) and the mixture was filtered through a pad ofCelite®, which was then washed with additional EtOAc (50 mL). Thefiltrate was evaporated to dryness and the residue was purified by flashchromatography (ISCO, 0 to 100% EtOAc-hexane) to afford4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-2-carbonitrile(0.600 g, 1.297 mmol, 57.8% yield) as a light brown oil. LC-MS (MethodH): 1.553 min, (M+H)=463.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.91 (d,J=8.2 Hz, 1H), 7.49-7.62 (m, 4H), 7.23 (d, J=8.2 Hz, 2H), 6.95 (s, 1H),5.53 (s, 2H), 2.80 (q J=7.4 Hz, 2H), 2.51 (hidden, 6H), 1.23 (t, J=7.4Hz, 3H), 0.22 (s, 9H).

Intermediate 234d:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-ethynyl-[1,1′-biphenyl]-2-carbonitrile

To a solution of4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-2-carbonitrile(0.600 g, 1.297 mmol) in THF (15 mL) and MeOH (15 mL) was added K₂CO₃(0.538 g, 3.890 mmol) and the mixture was stirred at RT for 3 h. Theresulting mixture was filtered through a pad of Celite®, which wassubsequently washed with EtOAc (100 mL). The filtrate was evaporated todryness to provide4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-ethynyl-[1,1′-biphenyl]-2-carbonitrile(0.535 g, 1.232 mmol, 95% yield) as a brown foam which was used as suchin the next step. LC-MS (Method H): 1.310 min, [M+H]⁺=391.1; ¹H NMR (400MHz, CDCl₃) δ 7.71 (d, J=8.2 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.50-7.54(m, 1H), 7.45-7.50 (m, 2H), 7.25 (d, J=8.2 Hz, 2H), 6.92 (s, 1H), 5.53(s, 2H), 3.48 (s, 1H), 2.83 (q, J=7.4 Hz, 2H), 2.66 (s, 3H), 2.61 (s,3H), 1.34 (t, J=7.4 Hz, 3H).

Intermediate 234e:5-(1-Ethyl-1H-1,2,3-triazol-4-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

To a mixture of4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-ethynyl-[1,1′-biphenyl]-2-carbonitrile(0.030 g, 0.077 mmol) and excess azidoethane [prepared by reacting asolution of bromoethane (0.250 g, 2.294 mmol) and sodium azide (0.373 g,5.740 mmol) in 5 mL of DMSO for 4 h at RT; the mixture was filtered andthe DMSO solution of the alkyne was used as such] in DMSO (4 mL) and H₂O(2 mL) was added sodium ascorbate (0.0034 g, 0.015 mmol) and CuSO₄.5H₂O(0.0013 g, 0.004 mmol). The reaction was stirred at RT for 16 h and thenit was poured into a mixture of saturated aqueous NH₄Cl (10 mL) andEtOAc (25 mL). The aqueous layer was separated and re-extracted withEtOAc (30 mL) and then the combined organic extract was washed (H₂O andbrine), dried (Na₂SO₄) and evaporated to provide5-(1-ethyl-1H-1,2,3-triazol-4-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.025 g, 0.054 mmol, 70.5% yield) as an oil which was used as such forthe next reaction. LC-MS (Method H): 1.272 min, (M+H)=462.2.

Example 234:2-Ethyl-3-((5′-(1-ethyl-1H-1,2,3-triazol-4-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

To a mixture of5-(1-ethyl-1H-1,2,3-triazol-4-yl)-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.025 g, 0.054 mmol), TMS-N₃ (0.151 mL, 1.083 mmol) and dibutyltinoxide (0.0275 g, 0.108 mmol) was added toluene (2 mL), the vial wasbriefly purged with N₂ and then it was sealed and heated at 120° C. for16 h. The cooled mixture was evaporated to give a gum which was purifiedby preparative LC (Method F) to give the title compound (0.007 g, 25.6%yield) as a white solid. HRMS (ESI): Calcd. for C₃₀H₂₈N₇O [M+H]⁺ m/z505.2571; found 505.2584. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.74 (s, 1H),7.95 (br s, 1H), 7.86 (br s, 1H), 7.72 (br s, 1H), 7.08-7.15 (m, 1H),7.04 (br s, 2H), 6.95 (s, 1H), 6.53 (s, 1H), 5.46 (s, 2H), 4.43 (q,J=7.4 Hz, 2H), 2.78 (q, J=7.7 Hz, 3H), 2.54 (hidden, 6H), 1.55 (t, J=7.4Hz, 4H), 1.25 (t, J=7.7 Hz, 3H).

The following examples have been similarly prepared from4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-ethynyl-[1,1′-biphenyl]-2-carbonitrile(Intermediate 234d) as described for the synthesis of Example 234 above.Two analytical LC-MS injections were used to determine the final purity.The retention time of one of them is reported for each compound and isreferred as Method H.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW (MethodH) δ ppm 235

520.5  521.2; 1.161 min 8.75 (s, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.97 (s,1H), 7.74 (d, J = 7.8 Hz, 1H), 7.03-7.14 (m, 4H), 6.96 (s, 1H), 5.47 (s,2H), 5.08 (t, J = 5.3 Hz, 1H), 4.46 (t, J = 5.3 Hz, 2H), 3.79-3.87 (m,2H), 2.77 (q, J = 7.4 Hz, 2H), 2.55 (s, 6H), 1.23 (t, J = 7.4 Hz, 3H).236

518.6  519.30; 1.241 min 8.75 (s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.90(s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.01-7.18 (m, 4 H), 6.95 (s, 1H),6.53 (s, 1H), 5.46 (s, 2H), 4.37 (t, J = 6.8 Hz, 2H), 2.78 (q, J = 7.4Hz, 2H), 2.50 (s, 6 H), 1.78-1.93 (m, 2H), 1.24 (t, J = 7.4 Hz, 6H). 237

530.58 531.30; 1.25 min (MeOH-d₄) 8.55 (s, 1H), 7.92- 8.04 (m, 2H), 7.73(d, J = 8.6 Hz, 1H), 7.20 (d, 7 = 8.2 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H),7.04 (s, 1H), 5.57 (s, 2H), 4.33 (d, J = 7.0 Hz, 2H), 2.87 (q, J = 7.4Hz, 2H), 2.54 (s, 3H), 2.69 (s, 3H), 1.40 (m, 1H), 1.27 (t, J = 7.6 Hz,3H), 0.64-0.75 (m, 2H), 0.47-0.56 (m, 2H). 238

566.5  567.2; 1.292 min (MeOH-d₄) 8.52 (s, 1 H), 7.97- 8.06 (m, 2H),7.75 (d, J = 8.2 Hz, 1H), 7.36-7.44 (m, 3 H), 7.32 (s, 1H), 7.28 (d, J =8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 5.74 (s, 2H), 5.68 (s, 2H), 3.12(d, J = 7.4 Hz, 2H), 2.67 (s, 6H), 1.33 (t, J = 7.4 Hz, 3H). 239

522.5  523.20; 1.186 min (MeOH-d₄) 8.52 (s, 1 H), 8.29 (br. s., 1H),7.88-8.00 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 2H),7.06 (m, 2H), 5.56 (s, 2H), 4.91-4.99 (m, 1H) 4.72-4.86 (m, 3H), 2.87(q, J = 7.4 Hz, 2H), 2.62 (s, 3H), 2.59 (s, 3H), 1.27 (t, J = 7.4 Hz,3H). 240

532.6  533.2 1.313 min (MeOH-d₄) 8.47 (s, 1H), 7.91- 8.01 (m, 2H), 7.70(d, J = 7.8 Hz, 1H), 7.11-7.20 (m, 2H), 7.00-7.11 (m, 3H), 5.56 (s, 2H),4.29 (d, J = 7.4 Hz, 2H), 2.87 (q, J = 7.7 Hz, 3H), 2.62 (s, 3H), 2.59(s, 3H), 2.22-2.34 (m, 2H), 1.27 (t, J = 7.4 Hz, 3H), 0.93 - 1.01 (m,6H). 241

532.2  533.2; 1.313 min (MeOH-d₄) 8.48 (s, 1H), 7.94- 7.99 (m, 2H), 7.70(d, J = 7.8 Hz, 1H), 7.13-7.19 (d, J = 8.2 Hz, 2H), 7.05-7.11 (m, J =8.2 Hz, 2H), 7.04 (s, 1H), 5.56 (s, 2H), 4.48 (m, 2H), 2.87 (q, J = 7.4Hz, 2H), 2.59 (s, 3H), 2.62 (s, 3H), 1.92-2.00 (m, 2H), 1.40 (dd, J =7.04, 14.87 Hz, 2H), 1.27 (t, J = 7.4 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).242

540.2  541.2; 1.200 min 8.81 (s, 1H), 7.97 (s, 1H), 7.75 (d, J = 7.8 Hz,1H), 7.13 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H),6.53 (t, J = 64.0 Hz 1H), 5.47 (s, 1H), 5.02 (dt, J = 3.1, 15.8 Hz, 2H),2.78 (q, J = 7.4 Hz, 1H), 2.50 (hidden, 6H), 1.24 (t, J = 1.4 Hz, 2H)

Example 243:2-Ethyl-5,7-dimethyl-3-((5′-(1-methyl-1H-1,2,3-triazol-4-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 243a:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-2-carbonitrile

To a mixture of4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-ethynyl-[1,1′-biphenyl]-2-carbonitrile(Intermediate 234d, 0.030 g, 0.077 mmol) and(azidomethyl)trimethylsilane (0.0198 g, 0.154 mmol) in t-Bu₀H—H₂O (3:1)was added sodium ascorbate (0.006 g, 0.031 mmol) and CuSO₄.5H₂O (0.0014g, 0.008 mmol). The reaction mixture was stirred at RT for 16 h and thenit was poured into saturated aqueous NH₄Cl (10 mL). The resultingmixture was extracted with EtOAc (25 mL) and the organic phase waswashed (H₂O, brine), dried (Na₂SO₄) and evaporated to dryness to afford4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-2-carbonitrile(0.030 g, 0.077 mmol, 75% yield). LC-MS (Method H): 1.339 min,[M+H]⁺=520.2. This material was used as such for next reaction.

Intermediate 243b:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-2-carbonitrile

To an ice-cold solution of4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(1-((trimethylsilyl)methyl)-1H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-2-carbonitrile(0.030 g, 0.058 mmol) in THF (4 mL) was added TBAF (1M in THF, 0.231 mL,0.231 mmol). The reaction mixture was stirred at RT for 1 h before beingquenched with saturated aqueous NH₄Cl (5 mL). This mixture was extractedwith EtOAc (25 mL) and the organic extract was separated, dried (Na₂SO₄)and evaporated to dryness. The crude the residual gum obtained waspurified by preparative LC (Method F) to provide4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-2-carbonitrile(0.015 g, 0.034 mmol, 58% yield). LC-MS (Method H): 1.262 min,[M+H]⁺=448.2.

Example 243:2-Ethyl-5,7-dimethyl-3-((5′-(1-methyl-1H-1,2,3-triazol-4-yl)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

To a mixture of4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(1-methyl-1H-1,2,3-triazol-4-yl)-[1,1′-biphenyl]-2-carbonitrile(0.015 g, 0.034 mmol), TMS-N₃ (0.094 mL, 0.670 mmol) and dibutyltinoxide (0.017 g, 0.067 mmol) was added toluene (2 mL), the vial wasbriefly purged with N₂ and then it was sealed and the mixture wasstirred at 120° C. for 16 h. The cooled mixture was evaporated to give agum which was purified by preparative LC (Method F) to afford the titlecompound (0.006 g, 36.5% yield) as a white solid. HRMS (ESI): Calcd. forC₂₇H₂₇N₁₀ [M+H]⁺ m/z 491.2420; found 491.2498. ¹H NMR (400 MHz, MeOH-d4)δ ppm 8.45 (s, 1H), 7.94-8.05 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.48 (s,1H), 7.15-7.34 (m, 4H), 5.72 (s, 2H), 4.19 (s, 3H), 3.11 (q, J=7.4 Hz,2H), 2.60 (s, 3H), 2.71 (s, 3H), 1.32 (t, J=7.4, 3H).

Example 244:4″-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N-(methylsulfonyl)-[1,1′:3′,1′-terphenyl]-4′-carboxamide

A solution of4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylicacid (Ex. 031, 0.030 g, 0.065 mmol) in DMF (1 mL) was treated with HATU(0.023 g, 0.078 mmol), followed by methanesulfonamide (0.007 g, 0.078mmol) and Hüinig's Base (0.023 mL, 0.130 mmol). After stirring at RT for18 h the solution was poured into H₂O (3 mL) and extracted with EtOAc(20 mL). The EtOAc layer was washed with H₂O and brine, dried (Na₂SO₄)and concentrated. The crude residual gum was purified by preparative LC(Method F) to afford the title compound (0.008 g, 0.015 mmol, 22.3%yield). LC-MS (Method H): 1.324 min, (M+H)=539.2; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.89 (d, J=7.8 Hz, 1H), 7.69 (dd, J=8.2, 1.6 Hz, 1H), 7.61(d, J=7.4 Hz, 2H), 7.57 (s, 1H), 7.44-7.50 (m, 2H), 7.37-7.44 (m, 3H),7.23-7.29 (m, 2H), 6.91 (s, 1H), 5.55 (s, 2H), 3.13 (s, 3H), 2.84 (q,J=7.4 Hz, 2H), 2.65 (s, 3H), 2.60 (s, 3H), 1.37 (t, J=7.4 Hz, 3H).

Example 245:3-(4″-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-1,2,4-thiadiazol-5(4H)-one

Intermediate: 245a:(Z)-4″-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N′-hydroxy-[1,1′:3′,1″-terphenyl]-4′-carboximidamide

Hydroxylamine hydrochloride (0.785 g, 11.30 mmol) was added to a vialcontaining4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile(032b, 0.200 g, 0.452 mmol) and 1-butyl-3-methylimidazolium acetate(3.00 g, 15.13 mmol). This mixture was heated at 50° C. for 18 h andthen it was allowed to cool to RT. DMSO (1 mL) was added, followed byH₂O (0.5 mL) and formic acid (0.06 mL, 15.13 mmol) to acidify to a pH ofabout 4. The solution was submitted to purification by preparative LC(Method F) to provide(Z)-4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N′-hydroxy-[1,1′:3′,1″-terphenyl]-4′-carboximidamide(0.120 g, 0.252 mmol, 55.8% yield). LC-MS (Method H): 1.229 min,(M+H)=476.2; ¹H NMR (400 MHz, CDCl₃) δ ppm 7.53-7.68 (m, 5H), 7.41-7.49(m, 4H), 7.34-7.40 (m, 1H), 7.20 (d, J=7.8 Hz, 2H), 6.92 (s, 1H), 5.51(s, 2H), 4.48 (br s, 2H), 4.48 (br s, 2H), 2.83 (q, J=7.4 Hz, 2H), 2.65(s, 3H), 2.61 (s, 3H), 1.32 (t, J=7.4 Hz, 3H).

Example 245:3-(4″-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-1,2,4-thiadiazol-5(4H)-one

To a solution of(Z)-4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-N′-hydroxy-[1,1′:3′,1″-terphenyl]-4′-carboximidamide(0.100 g, 0.210 mmol) in anhydrous THF (2 mL), at RT under N₂, was addeddi(1H-imidazol-1-yl)methanethione (0.056 g, 0.315 mmol) and the solutionwas stirred at 35° C. for 1 h. The reaction was then quenched with H₂Oand extracted with EtOAc (25 mL). The organic extract was dried (Na₂SO₄)filtered, and evaporated to dryness. The crude residue obtained wasdissolved in anhydrous THF (2 mL), then BF₃.OEt₂ (0.167 mL, 0.631 mmol)was added dropwise and the resulting mixture was stirred at RT for 16 h.The resulting mixture was diluted with H₂O and extracted with CH₂Cl₂ (25mL). The organic extract was washed (1M HCl), dried (Na₂SO₄) andevaporated under reduced pressure. The residual gum obtained was takenup in DMF (1.8 mL) and purified by preparative LC (Method F) to give thetitle compound (0.013 g, 0.027 mmol, 13% yield) as a white solid. LC-MS(Method H): 1.374 min, (M+H)=518.1; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.99(d, J=7.8 Hz, 1H), 7.83-7.87 (m, 1H), 7.76-7.83 (m, 3H), 7.63 (d, J=8.2Hz, 2H), 7.37-7.51 (m, 3H), 7.29 (d, J=8.2 Hz, 2H) 6.99 (s, 1H), 5.57(s, 2H), 2.86 (q, J=7.4 Hz, 2H), 2.51 (s, 6H), 1.25 (t, J=7.4 Hz, 3H).

Example 246:5-(4″-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-1,3,4-oxadiazole-2(3H)-thione

Intermediate 246a:4″-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbohydrazide

To a mixture of4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylicacid (Ex. 031, 0.100 g, 0.217 mmol), HATU (0.099 g, 0.260 mmol), andhydrazine (1.0M in THF, 0.260 mL, 0.260 mmol) in DMF (1.30 mL) was addedHüinig's base (0.076 mL, 0.433 mmol) and the mixture was stirred at RTfor 18 h. The resulting mixture was poured into H₂O (3 mL) and wasextracted with EtOAc (25 mL). The organic extract was washed (H₂O,brine), dried (Na₂SO₄) and evaporated to dryness. The residue obtainedwas purified by prep LC (Method F) to give4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbohydrazide(0.081 g, 0.170 mmol, 79% yield). LC-MS (Method H): 1.344 min,(M+H)=476.2; ¹H NMR (400 MHz, CDCl₃) δ ppm 8.03 (s, 1H), 7.70-7.77 (m,1H), 7.65 (dd, J=8.0, 1.8 Hz, 1H), 7.59-7.63 (m, 2H), 7.55 (d, J=1.6 Hz,1H), 7.43-7.50 (m, 2H), 7.36-7.43 (m, 3H), 7.21 (d, J=7.8 Hz, 2H), 6.93(s, 1H), 5.53 (s, 2H), 2.97 (s, 1H), 2.90 (s, 1H), 2.78-2.89 (m, 2H),2.65 (s, 3H), 2.62 (s, 3H), 1.34 (t, J=7.4 Hz, 3H).

Example 246:5-(4″-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-1,3,4-oxadiazole-2(3H)-thione

To a solution of4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbohydrazide(0.015 g, 0.032 mmol) in ethanol (0.2 mL) was added CS₂ (0.002 mL, 0.033mmol) and KOH (0.002 g, 0.032 mmol) at 0° C. The resulting solution washeated at reflux for 12 h and then the volatiles were removed underreduced pressure and the residue was dissolved in H₂O and the solutionwas acidified with dilute aqueous HCl. This mixture was evaporated andthe residual gum was submitted to prep LC (Method F) to give the titlecompound (0.0073 g, 0.014 mmol, 44.7% yield). LC-MS (Method H): 1.495min, (M+H)=518.1, ¹H NMR (400 MHz, CDCl₃) δ ppm 7.95 (d, J=8.2 Hz, 1H),7.72 (d, J=7.8 Hz, 1H), 7.59-7.68 (m, 3H), 7.38-7.52 (m, 3H), 7.30 (d,J=7.8 Hz, 2H), 7.17 (d, J=7.4 Hz, 2H), 6.93 (s, 1H), 5.52 (br s, 2H),2.77 (q, J=7.4 Hz, 2H), 2.60 (s, 3H), 2.56 (s, 3H), 1.04 (t, J=7.4 Hz,3H).

Example 247:2-Ethyl-5,7-dimethyl-3-((5′-(pyridin-2-yloxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

Intermediate 247a:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-hydroxy-[1,1′-biphenyl]-2-carbonitrile

In a 75-mL vial, a stream of Ar was passed through a mixture ofIntermediate 001d (0.35 g, 0.89 mmol), 2-bromo-4-hydroxybenzonitrile(0.21 g, 1.07 mmol) and 2M Na₂CO₃ (1.3 mL, 2.7 mmol) in toluene (6 mL)and ethanol (0.6 mL). After 5 minutes, Pd (PPh₃)₄ (0.052 g, 0.045 mmol)was added, Ar was bubbled through the mixture for an additional 5 minand the sealed vial was heated at 95° C. for 16 h. The mixture was thenallowed to cool to RT and saturated aqueous ammonium chloride (20 mL)and EtOAc (20 mL) were added. The aqueous layer was separated andextracted with EtOAc (2×20 mL), and the combined organic layers werewashed with brine, dried (anhydrous MgSO₄), filtered and evaporated. Theresidue was triturated in DCM and the precipitate was filtered to affordthe title compound (0.091 g). The mother liquor was evaporated and theresidue was purified using a 24 g-RediSep column (ISCO/0-100% EtOAc-DCM)to afford another 0.069 g of the title compound which was combined withthe material obtained from trituration to give 0.160 g (47% yield) ofthe desired product. LC-MS (Method H): 1.29 min, [M+H]⁺=383.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 10.75 (br s, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.47(d, J=8.2 Hz, 2H), 7.22 (d, J=8.2 Hz, 2H), 6.94 (s, 1H), 6.89 (dd,J=8.6, 2.4 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 5.52 (s, 2H), 2.80 (q, J=7.4Hz, 2H), 2.51 (s, 6H), 1.24 (t, J=7.4 Hz, 3H).

Intermediate 247b:4′-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(pyridin-2-yloxy)-[1,1′-biphenyl]-2-carbonitrile

In a conical 2-mL vial, a stream of Ar was passed through a suspensionof4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-hydroxy-[1,1′-biphenyl]-2-carbonitrile(0.044 g, 0.11 mmol), 2-chloropyridine (0.032 mL, 0.34 mmol) and cesiumcarbonate (0.110 g, 0.34 mmol) in toluene (0.4 mL). After 5 min,palladacycle precatalyst J009 PreCat (2.0 mg, 2.2 μmol) was added and Arwas bubbled through the mixture for an additional 5 min. The sealed vialwas then heated at 100° C. for 24 h and allowed to cool to RT. Saturatedaqueous ammonium chloride (5 mL) and EtOAc (10 mL) were added and theseparated aqueous layer was extracted with EtOAc (2×10 mL). The combinedorganic layers were washed with brine, dried (anhydrous MgSO₄), filteredand evaporated. The residue was purified using a 24 g-RediSep column(ISCO/0-100% EtOAc-DCM) to afford4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(pyridin-2-yloxy)-[1,1′-biphenyl]-2-carbonitrile(0.026 g, 50% yield). LC-MS (Method H): 1.37 min, [M+H]⁺=460.2. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.18 (dd, J=5.1, 2.0 Hz, 1H), 7.88 (dd, J=7.4,1.6 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.50-7.56 (m, 2H), 7.26 (m, 4H),7.11 (d, J=8.3 Hz, 1H), 7.03 (s, 1H), 5.62 (s, 2H), 2.89 (q, J=7.5 Hz,2H), 2.61 (s, 3H), 2.58 (s, 3H), 1.28 (t, J=7.5 Hz, 3H).

Example 247:2-Ethyl-5,7-dimethyl-3-((5′-(pyridin-2-yloxy)-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-3H-imidazo[4,5-b]pyridine

In a conical 2-mL vial was added4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-(pyridin-2-yloxy)-[1,1′-biphenyl]-2-carbonitrile(0.020 g, 0.044 mmol), dibutyltin oxide (0.012 g, 0.048 mmol) and TMS-N₃(0.046 mL, 0.35 mmol) in toluene (0.250 mL) and the sealed vial washeated at 100° C. for 12 h. The mixture was allowed to cool to RT andthe volatiles were then removed under reduced pressure. The residue wasdissolved in DMSO and filtered through a 0.46 μm syringe filter andpurified by preparative HPLC (Method D) to afford the title compound.(0.0133 g, 61% yield). LC-MS (Method H): 1.30 min, [M+H]⁺=503.2; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.22 (m, 1H), 7.90 (m, 1H), 7.68 (d, J=8.6 Hz,1H), 7.28-7.34 (m, 1H), 7.25 (d, J=2.4 Hz, 1H), 7.19 (m, 1H), 7.15 (m,1H), 7.04 (m, 4H), 6.94 (s, 1H), 5.44 (s, 2H), 2.74 (q, J=7.6 Hz, 2H),2.51 (s, 6H), 1.20 (t, J=7.6 Hz, 3H).

The following examples have been similarly prepared from Intermediate247a as described above for Example 247.

In Example 249,4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-hydroxy-[1,1′-biphenyl]-2-carbonitrileis reacted, as described above, with tert-butyl(2-chloropyridin-4-yl)carbamate instead of 2-chloropyridine. Theresulting Intermediate 007b was obtained. In the subsequent step,Boc-deprotection was concomitant to tetrazole formation to afford Ex.249.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW (MethodH) δ ppm 248

516.60 517.20; 1.30 min 8.01 (m, 1H), 7.72 (dd, J = 8.2, 2.7 Hz, 1H),7.66 (d, J = 8.2 Hz, 1H), 7.26 (m, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.04(m, 5H), 6.94 (s, 1H), 5.43 (s, 2H), 2.74 (q, J = 7.6 Hz, 2 H), 2.49 (s,6H), 2.25 (s, 3H), 1.20 (t, J = 7.6 Hz, 3H) 249

517.58 518.20; 1.11 min 7.63 (m, 2H), 7.20 (dd, J = 8.6, 2.8 Hz, 1H),7.13 (d, J = 2.4 Hz, 1H), 7.03 (m, 4H), 6.94 (s, 1H), 6.31 (dd, J = 5.9,2.0 Hz, 1H), 6.23 (s, 2H), 6.09 (d, J = 2.0 Hz, 1H), 5.43 (s, 2H), 2.74(q, J = 7.6 Hz, 2 H), 2.52 (s, 6H), 1.21 (t, J = 7.6 Hz, 3H) 250

516.60 517.20; 1.29 min 8.04 (d, J = 5.5 Hz, 1H), 7.67 (d, J = 8.6 Hz,1H), 7.28 (m, 1H), 7.21 (d, J = 2.3 Hz, 1H), 7.04 (m, 5H), 7.01 (m, 1H),6.94 (s, 1H), 5.44 (s, 2H), 2.74 (q, J = 7.6 Hz, 2 H), 2.50 (s, 6H),2.35 (s, 3H), 1.20 (t, J = 7.6 Hz, 3H) 251

537.02 537.10; 1.36 min 8.16 (d, J = 5.5 Hz, 1H), 7.70 (d, J = 8.6 Hz,1H), 7.33 (m, 4H), 7.04 (m, 4H), 6.94 (s, 1H), 5.44 (s, 2H), 2.74 (q, J= 7.4 Hz, 2 H), 2.50 (s, 6H), 1.20 (t, J = 7.4 Hz, 3H) 252

508.60 509.10; 1.26 min 7.73 (d, J = 8.2 Hz, 1H), 7.52 (dd, J = 8.2, 2.3Hz, 1H), 7.47 (d, J = 2.7 Hz, 1H), 7.30 (m, 2H), 7.04 (m, 4H), 6.93 (s,1H), 5.43 (s, 2H), 2.74 (q, J = 7.4 Hz, 2H), 2.51 (s., 6H), 1.19 (t, J =7.4 Hz, 3H) 253

520.56 521.20; 1.27 min 7.99 (d, J = 4.7 Hz, 1H), 7.90 (t, J = 9.0 Hz,1H), 7.70 (d, J = 8.6 Hz, 1H), 7.37 (dd, J = 8.6, 2.4 Hz, 1 H), 7.33 (d,J = 2.4 Hz, 1 H), 7.25 (m, 1H), 7.04 (m, 4H), 6.94 (s, 1H), 5.44 (s,2H), 2.74 (q, J = 7.4 Hz, 2H), 2.51 (s., 6H), 1.19 (t, J = 7.4 Hz, 3H)254

520.56 521.20; 1.28 min 8.20 (dd, J = 9.0, 5.9 Hz, 1 H), 7.68 (d, J =8.6 Hz, 1 H), 7.33 (dd, J = 8.6, 2.4 Hz, 1 H), 7.28 (d, J = 2.4 Hz, 1H), 7.14 (m, 2H), 7.04 (m, 4H), 6.94 (s, 1H), 5.43 (s, 2H), 2.74 (q, J =7.4 Hz, 2H), 2.51 (s., 6H), 1.21 (t, J = 7.4 Hz, 3H) 255

537.02 537.20; 1.30 min 8.23-8.02 (m, 2 H), 7.70 (d, J = 8.6 Hz, 1 H),7.35 (m, 1 H), 7.30 (d, J = 2.4 Hz, 1 H), 7.22 (dd, J = 7.8, 4.7 Hz, 1H), 7.04 (m, 4H), 6.94 (s, 1H), 5.44 (s, 2H), 2.74 (q, J = 7.4 Hz, 2H),2.50 (s., 6H), 1.20 (t, J = 7.4 Hz, 3H) 256

520.56 521.10; 1.27 min (MeOH-d₄): 7.95 (m, 1 H), 7.70 (d, J = 8.2 Hz, 1H), 7.29 (m, 2 H), 7.09 (m, 4H), 7.03 (s, 1 H), 6.96 (m, 1H), 6.78 (m,1H), 5.55 (s, 2H), 2.85 (q, J =7.8 Hz, 2H), 2.60 (s., 3H), 2.57 (s, 3H),1.25 (t, J = 7.8 Hz, 3H)

The following examples were prepared from4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile(Intermediate 205a) and the appropriate 3-hydroxypyridine or3-hydroxypyrimidine, using a method similar to that described for thesynthesis of Intermediate 205b and Example 205. Example 259 was preparedaccording to the method described for the synthesis of Example 214.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d6) Ex Structure MW (MethodH) δ ppm 257

502.57 503.10; 1.28 min (MeOH-d₄): 8.81 (m, 2H), 7.69 (d, J = 9.0 Hz,1H), 7.61 (d, J =1.6 Hz, 1H), 7.50 (m, 1H), 7.19 (m, 2H) 7.08 (m, 4H),7.05 (s, 1H), 5.56 (s, 2H), 2.86 (q, J = 7.6 Hz, 2H), 2.61 (s, 3H), 2.58(s, 3H), 1.25 (t, J = 7.6 Hz, 3H) 258

503.56 504.20; 1.25 min 9.06 (s, 1H) 8.78 (s, 2H) 7.70 (d, J = 8.22 Hz,1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.26 (m, 1H), 7.05 (m, 4H), 6.94(s, 1H), 5.44 (s, 2H), 2.74 (q, J = 7.6 Hz, 2 H), 2.50 (s, 6H), 1.21 (t,J = 7.6 Hz, 3H) 259

518.56 519.10; 1.81 min 8.45 (d, J = 2.74 Hz, 2 H), 7.83 (d, J = 8.61Hz, 1 H), 7.38-7.43 (m, 1H), 7.32-7.37 (m, 1 H), 7.25 (d, J = 8.22 Hz, 2H), 7.17 (d, J = 8.22 Hz, 2 H), 7.07 (dd, J = 8.61, 2.35 Hz, 1 H), 6.96(d, J = 2.35 Hz, 1 H), 6.90 (s, 1 H), 5.49 (s, 2 H), 2.81 (q, J = 7.70Hz, 2 H), 2.62 (s, 3 H), 2.57 (s, 3 H), 1.34 (t, J = 7.63 Hz, 3 H) 260

516.60 517.20; 1.28 min 8.28 (m, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.44(br. S, 1H), 7.15 (dd, J = 8.2, 2.4 Hz, 1H), 7.11 (m, 1H), 7.02 (m, 4H),6.92 (s, 1H), 5.42 (s, 2H), 2.72 (q, J = 7.6 Hz, 2 H), 2.49 (s, 6H),2.29 (s, 3H), 1.19 (t, J = 7.6 Hz, 3H) 261

532.60 533.20; 1.30 min 8.20 (d, J = 2.4 Hz, 1H), 8.08 (d, J = 2.3 Hz,1H), 7.68 (d, J = 8.6 Hz, 1H), 7.29 (m, 1H), 7.23 (m, 1H), 7.15 (m, 1H),7.04 (m, 4H), 6.95 (s, 1H), 5.44 (s, 2H), 3.83 (s, 3H), 2.74 (q, J = 7.4Hz, 2 H), 2.51 (s, 6H), 1.21 (t, J = 7.4 Hz, 3H) 262

520.56 521.20; 1.36 min (MeOH-d₄) : 8.06 (m, 1 H), 7.79 (m, 1H), 7.68(d, J = 8.6 Hz, 1 H), 7.40 (m, 1 H), 7.21 (m, 3H), 7.13 (m, 4H), 5.67(s, 2H), 3.04 (q, J = 7.4 Hz, 2H), 2.65 (s., 3H), 2.64 (s, 3H), 1.30 (t,J = 7.4 Hz, 3H)

Example 264:2-ethyl-3-((3-fluoro-6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 264a:(4-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3-fluorophenyl)boronicacid, TFA salt

Intermediate 264a was prepared in a similar manner as for Intermediate001d, by replacing2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane with2-(4-(bromomethyl)-3-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.Intermediate 264a was purified by preparative HPLC (method E). LC-MS(Method A5): 0.62 min, [M+H]⁺=328.0; ¹H NMR (400 MHz, MeOH-d4) δ7.54-7.42 (m, 2H), 7.39 (s, 1H), 7.30 (t, J=7.6 Hz, 1H), 5.83 (s, 2H),3.26 (q, J=7.7 Hz, 2H), 2.72-2.66 (m, 6H), 1.41 (t, J=7.6 Hz, 3H).

Intermediate 264b:5-chloro-4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3′-fluoro-[1,1′-biphenyl]-2-carbonitrile

Intermediate 264a was reacted with 4-chloro-2-iodobenzonitrile in amanner analogous to Intermediate 177d to give Intermediate 264b. LC-MS(Method A5): 0.85 min, [M+H]⁺=419.0. ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d,J=8.1 Hz, 1H), 7.49-7.41 (m, 2H), 7.35-7.30 (m, 1H), 7.23-7.15 (m, 1H),7.00 (t, J=7.8 Hz, 1H), 6.92 (s, 1H), 5.58 (s, 2H), 2.87 (q, J=7.6 Hz,2H), 2.65 (s, 3H), 2.61 (s, 3H), 1.38 (t, J=7.5 Hz, 3H).

Intermediate 264c:4″-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-3″-fluoro-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

Intermediate 264b was reacted with phenyllboronic acid in a manneranalogous to Intermediate 177e to give Intermediate 264c. LC-MS (MethodA5): 0.93 min, [M+H]⁺=461.1; ¹H NMR (500 MHz, CDCl₃) δ 7.83 (d, J=8.0Hz, 1H), 7.70-7.66 (m, 2H), 7.61 (d, J=7.4 Hz, 2H), 7.53-7.42 (m, 3H),7.39 (dd, J=10.6, 1.5 Hz, 1H), 7.29-7.24 (m, 1H), 7.02 (t, J=7.7 Hz,1H), 6.93 (s, 1H), 5.60 (s, 2H), 2.89 (q, J=7.7 Hz, 2H), 2.66 (s, 3H),2.62 (s, 3H), 1.39 (t, J=7.4 Hz, 3H).

Example 264:2-ethyl-3-((3-fluoro-6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridine

Intermediate 264c was reacted with dibutyltin oxide and TMS-N₃ in amanner analogous to Example 177 to give Example 264. LC-MS (Method A4):1.70 min, [M+H]⁺=504.22; ¹H NMR (500 MHz, DMSO-d₆) δ 7.82-7.77 (m, 2H),7.75 (s, 2H), 7.63 (s, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.43-7.38 (m, 1H),7.10 (br d, J=11.3 Hz, 1H), 6.99-6.94 (m, 2H), 6.69 (br t, J=7.9 Hz,1H), 5.50 (s, 2H), 3.40 (br s, 3H), 2.83 (q, J=7.3 Hz, 2H), 1.93 (s,3H), 1.30 (t, J=7.5 Hz, 3H).

Examples 265-267 were prepared using the methods described for Example264:

LCMS m/z [M + H]⁺; ¹H NMR (400 MHz, Ex Structure MW RT (Method) DMSO-d6)δ ppm 265

503.58 504.23; 1.66 min (Method A4) 7.92 (s, 2H), 7.80 (d, J = 7.7 Hz,2H), 7.72 (s, 1H), 7.53- 7.47 (m, 2H), 7.46-7.40 (m, 1H), 7.36 (t, J =7.8 Hz, 1H), 6.98 (s, 1H), 6.94 (d, J = 9.0 Hz, 2H), 5.51 (s, 2H), 2.83(q, J = 7.5 Hz, 2H), 2.54 (s, 3H), 2.53 (s, 3H), 1.29 (t, J = 7.5 Hz,3H). 266

517.24 518.05; 1.81 min (Method A4) 7.96 (s, 1H), 7.83 (br d, J = 7.9Hz, 1H), 7.79-7.74 (m, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 7.59 (br d, J =7.9 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.24 (br d, J = 7.6 Hz, 1H), 7.14(br d, J = 11.3 Hz, 1H), 6.96 (s, 1H), 6.90 (br d, J = 7.9 Hz, 1H), 6.74(br t, J = 7.8 Hz, 1H), 5.50 (s, 2H), 2.80 (q, J = 7.3 Hz, 2H), 2.56 (s,6H), 2.39 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H). 267

517.24 518.22; 1.78 min (Method A4) 7.97-7.91 (m, 2H), 7.77 (br d, J =7.9 Hz, 1H), 7.58- 7.50 (m, 3H), 7.35 (t, J = 7.6 Hz, 1H), 7.25 (t, J =7.8 Hz, 1H), 7.20 (br d, J = 7.6 Hz, 1H), 6.97 (s, 1H), 6.93-6.85 (m,2H), 5.50 (s, 2H), 2.83 (q, J = 7.5 Hz, 2H), 2.54 (s, 3H), 2.53 (br s,3H), 1.92 (s, 3H), 1.29 (t, J = 7.3 Hz, 3H).

Example 268:2-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-2-methylpropanoicacid

Intermediate 268a: Methyl 2-((4-bromobenzyl)amino)-2-methylpropanoate

To a mixture of methyl 2-amino-2-methylpropanoate hydrochloride (0.538g, 3.50 mmol) in ACN (10 mL) was added 1-bromo-4-(bromomethyl)benzene(0.875 g, 3.5 mmol) and DIEA (1.22 mL, 7.00 mmol) and the mixture washeated at 80° C. for 3 h. The volatiles were then evaporated underreduced pressure and tert-butylmethyl ether (15 mL) and saturatedaqueous sodium hydrogen carbonate (5 mL) were added to the residue. Theaqueous phase was separated and re-extracted with tert-butylmethyl ether(10 mL), and the combined organic extract was dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by flash chromatography (12 g ISCO-type silica gelcolumn, 0 to 10% EtOAc/hexane gradient) to afford the title compound(0.716 g, 2.50 mmol, 71% yield) as a clear, colorless oil. LC-MS (MethodH): 0.96 min, [M+H]⁺=286.0; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.43-7.52(m, 2H), 7.24-7.33 (m, 2H), 3.62 (s, 3H), 3.54 (d, J=4.7 Hz, 2H), 2.47(br s, 1H), 1.19-1.30 (m, 6H).

Intermediate 268b: Methyl2-(N-(4-bromobenzyl)pentanamido)-2-methylpropanoate

To a solution of Intermediate 268a (0.350 g, 1.22 mmol) in EtOAc (3.5mL) was added DIEA (0.85 mL, 4.84 mmol) followed by pentanoyl chloride(0.22 mL, 1.84 mmol) and this mixture was heated at 65° C. for 18 h. Thecooled mixture was diluted with tert-butylmethyl ether (25 mL), washed(5 mL of 10% aqueous citric acid, then 5 mL of saturated aqueous sodiumhydrogen carbonate), dried (anhydrous sodium sulfate), filtered andevaporated under reduced pressure. The crude product was purified byflash chromatography (12 gram ISCO-type column using a 0 to 25%acetone/hexane gradient) to afford the title compound (0.716 g, 2.50mmol, 71% yield) as an orange crystalline solid. LC-MS (Method H): 1.34min, [M+H]⁺=370.0; ¹H NMR (DMSO-d₆) δ ppm 7.54-7.62 (m, 2H), 7.33-7.42(m, J=8.2 Hz, 2H), 4.64 (s, 2H), 3.58 (s, 3H), 2.11-2.23 (m, 2H),1.35-1.49 (m, 2H), 1.26 (s, 6H), 1.18 (dq, J=14.8, 7.3 Hz, 2H), 0.78 (t,J=7.2 Hz, 3H).

Intermediate 268c:3-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-4-carbonitrile

The title compound was prepared from [1,1′-biphenyl]-4-carbonitrileaccording to a literature procedure (cf. J. L. Kristensen, et al.Journal of Organic Chemistry, 2006, 71, 2518) to afford a white solid.¹H NMR (DMSO-d₆) δ ppm 8.04-8.08 (m, 1H), 7.88-7.91 (m, 2H), 7.67-7.74(m, 2H), 7.47-7.54 (m, 2H), 7.41-7.47 (m, 1H), 3.82 (s, 4H), 0.99 (s,6H).

Intermediate 268d: Methyl2-(N-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-2-methylpropanoate

Intermediate 268d was prepared by the reaction of Intermediate 268b(0.075 g, 0.258 mmol) with Intermediate 268c (0.114 g, 0.309 mmol),according to the method described for the synthesis of Intermediate330b. The title compound (0.100 g, 0.213 mmol, 83% yield) was isolatedas a white solid. LC-MS (Method H): 1.45 min, [M-C₅H₉O+H]=385.1; ¹H NMR(DMSO-d₆) δ ppm 8.03 (d, J=7.8 Hz, 1H), 7.80-7.93 (m, 4H), 7.68-7.77 (m,2H), 7.57-7.63 (m, 2H), 7.43-7.55 (m, 3H), 4.78 (s, 2H), 3.61 (s, 3H),2.25 (t, J=7.0 Hz, 2H), 1.37-1.55 (m, 2H), 1.32 (s, 6H), 1.10-1.29 (m,2H), 0.73-0.89 (m, 3H).

Example 268:2-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-2-methylpropanoicacid

To a pressure vial containing Intermediate 268d (0.045 g, 0.096 mmol)was added toluene (6 mL), dibutyltin oxide (0.024 g, 0.096 mmol) andazidotrimethylsilane (0.064 mL, 0.48 mmol). The reaction vessel wassealed and the mixture was heated at 110° C. for 18 h. The cooledmixture was then evaporated and the residue was taken up in DMSO (2.5mL). To this mixture was added 2.5M NaOH (0.66 mL, 0.96 mmol) and theresulting mixture was heated at 60° C. for 3 days. To the cooled mixturewas then added formic acid (0.072 mL, 1.92 mmol), the mixture wasfiltered and the filtrate was submitted to prep LC (Method F, TFA asmodifier). This afforded the title compound (0.031 g, 0.062 mmol, 64%yield) as a white solid. LC-MS (Method H): 1.34 min, 496.1; ¹H NMR(DMSO-d₆) δ ppm 11.95 (br s, 2H), 7.79-7.91 (m, 4H), 7.75 (d, J=7.8 Hz,1H), 7.48-7.57 (m, 2H), 7.41-7.48 (m, 1H), 7.36-7.41 (m, J=8.2 Hz, 2H),7.17-7.24 (m, 2H), 4.66 (s, 2H), 2.18 (t, J=7.2 Hz, 2H), 1.43 (dt,J=14.8, 7.3 Hz, 2H), 1.27 (s, 6H), 1.19 (dq, J=15.0, 7.4 Hz, 2H), 0.79(t, J=7.2 Hz, 3H).

The following examples were similarly prepared from the correspondingamino ester or amino ester hydrochloride salt as described for thesynthesis of Example 268 above. Analytical LC-MS injections were used todetermine the final purity and the retention time is reported for eachcompound and is referred as Method A1, Method A2 or Method H.

LC-MS m/z [M + H]⁺; ¹H NMR (400 MHz, Structure MW RT (Method) DMSO-d₆) δppm 269

495.58 496.1; 1.29 min (Method H) 7.79-7.89 (m, 3H), 7.70-7.79 (m, 2H),7.47-7.56 (m, 2H), 7.38-7.47 (m, 1H), 7.03-7.14 (m, 4H), 4.99 (d, J =16.0 Hz, 1H), 4.10 (d, J = 16.0 Hz, 1H), 2.52-2.60 (m, 1H), 2.22- 2.37(m, 1H), 1.66 (m, 1H), 1.37-1.59 (m, 3H), 1.14-1.37 (m, 1H), 0.98-1.12(m, 1H), 0.87 (t, J = 7.2 Hz, 3H) 270

509.61 510.2; 1.31 min (Method H) 12.41 (br. s., 2H), 7.78-7.91 (m, 4H),7.72-7.78 (m, 1H), 7.48-7.56 (m, 2H), 7.40-7.48 (m, 1H), 7.28-7.36 (m,2H), 7.22-7.28 (m, 2H), 4.54 (s, 2H), 2.45 (d, J = 9.4 Hz, 1H),2.03-2.26 (m, 3H), 1.84-2.03 (m, 1H), 1.67 (d, J = 10.2 Hz, 1H),1.35-1.61 (m, 3H), 1.10-1.34 (m, 3H), 0.77 (t, J = 7.4 Hz, 3H). 271

523.63 524.1; 1.32 min (Method H) 12.05 (s, 2H), 7.78-7.90 (m, 4H), 7.75(d, J = 7.8 Hz, 1H), 7.48-7.55 (m, 2H), 7.40-7.48 (m, 1H), 7.31-7.39 (m,2H), 7.17-7.24 (m, 2H), 4.64 (s, 2H), 2.21-2.32 (m, 2H), 2.16 (t, J =7.2 Hz, 2H), 1.61-1.75 (m, 2H), 1.48-1.61 (m, 4H), 1.43 (dt, J = 14.9,7.4 Hz, 2H), 1.18 (dq, J = 15.0, 7.3 Hz, 2H), 0.78 (t, J = 7.2 Hz, 3H).272

537.66 538.1; 1.34 min. (Method H) 11.93 (s, 2H), 7.78-7.90 (m, 4H),7.74 (d, J = 8.2 Hz, 1H), 7.47-7.56 (m, 2H), 7.41-7.47 (m, 1H),7.35-7.41 (m, 2H), 7.16-7.22 (m, 2H), 4.64 (m, 2H), 2.18 (t, J = 7.0 Hz,2H), 2.04 (d, J = 11.7 Hz, 2H), 1.51-1.68 (m, 4H), 1.36-1.51 (m, 6H),1.15-1.26 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H).

LC-MS m/z [M + H]⁺; ¹H NMR (400 MHz, Ex Structure MW RT (Method)DMSO-d₆) δ ppm 273

538.65 539.2; 1.300 min (Method H) 12.01 (s, 2H), 8.50 (s, 1H), 8.05 (d,J = 1.6 Hz, 1H), 7.90-8.00 (m, 2H), 7.73-7.90 (m, 3H), 7.67 (d, J = 8.2Hz, 1H), 7.49-7.57 (m, 2H), 7.40-7.49 (m, 1H), 4.76 (s, 2H), 2.20 (t, J= 6.8 Hz, 2H), 2.01 (d, J = 11.3 Hz, 2H), 1.38-1.70 (m, 9H), 1.06-1.33(m, 3H), 0.80 (t, J = 7.4 Hz, 3H). 274

538.65 539.2; 1.290 min (Method H) 12.10 (s, 2H), 8.44 (d, J = 2.0 Hz,1H), 7.92-7.99 (m, 1H), 7.81-7.92 (m, 4H), 7.72 (dd, J = 8.2, 2.3 Hz,1H), 7.49- 7.60 (m, 3H), 7.41-7.49 (m, 1H), 4.84 (s, 2H), 2.19 (t, J =6.7 Hz, 1H), 2.06 (d, J = 9.8 Hz, 1H), 1.36-1.74 (m, 9H), 1.08-1.35 (m,3H), 0.78 (t, J = 7.2 Hz, 3H).

Example 275:1-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentan-amido)-4,4-dimethylcyclohexanecarboxylicacid

Intermediate 275a: Methyl4,4-dimethyl-1-(((6′-(2-trityl-2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)amino)cyclohexanecarboxylate

To a solution of Intermediate I-004, 0.110 g, 0.174 mmol) in ACN (2.5mL) was added DIEA (0.121 mL, 0.694 mmol), followed by methyl1-amino-4,4-dimethylcyclohexanecarboxylate hydrochloride (0.058 g, 0.260mmol) and sodium iodide (0.130 g, 0.868 mmol) and the mixture was heatedat 65° C. for 5 h. To the cooled mixture was added H₂O (5 mL) and EtOAc(20 mL) and the organic layer was separated, washed (H₂O brine), dried(anhydrous sodium sulfate), filtered and evaporated. This afforded thetitle compound as a pale yellow foam (0.130 g) which was used as such inthe next step without further purification or characterization.

Example 275:1-(N-(((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentan-amido)-4,4-dimethylcyclohexanecarboxylicacid

To a solution of Intermediate 275a (0.128 g, 0.174 mmol) in anhydrousTHF (5 mL) was added sodium hydride (60% w/w in oil, 0.035 g, 0.870mmol) in one portion and the mixture was stirred for 5 min Pentanoylchloride (0.103 mL, 0.870 mmol) was then added and the mixture wasstirred at 50° C. for 6 h and then at RT for a further 18 h. Theresulting mixture was quenched with AcOH (0.100 mL, 1.75 mmol) and thenthe volatiles were evaporated and the residue was taken up intrifluoroacetic acid (1 ml) to give a clear yellow solution.Triisopropylsilane was then added in 10 μL portions until the colorfaded to give a pale yellow solution (required approximately 40 μL). Thevolatiles were again removed under reduced pressure and the residuetaken up in DMSO (3 mL) and was submitted to prep LC purification(Method F, TFA as modifier). This afforded the title compound (0.005 g,0.0083 mmol, 5% yield) as a white solid. LC-MS (Method H): 1.34 min,[M+H]⁺=566.1; ¹H NMR (DMSO-d₆) δ ppm 7.80-7.89 (m, 4H), 7.77-7.80 (m,1H), 7.48-7.55 (m, 2H), 7.43-7.48 (m, 1H), 7.38 (d, J=8.2 Hz, 2H), 7.21(d, J=8.2 Hz, 2H), 4.68 (s, 2H), 2.21 (t, J=7.2 Hz, 2H), 1.95 (m, 2H),1.37-1.66 (m, 6H), 1.09-1.34 (m, 4H), 0.71-0.85 (m, 9H).

The following examples were similarly prepared from the correspondingamino ester or amino ester hydrochloride salt as described for thesynthesis of Example 275 above. Analytical LC-MS injections were used todetermine the final purity and the retention time is reported for eachcompound and is referred as Method A1, Method A2 or Method H.

LC-MS m/z [M + H]⁺; ¹H NMR (400 MHz, Ex Structure MW RT (Method)DMSO-d₆) δ ppm 276

539.63 540.1; 1.31 min (Method H) 12.29 (br s, 2H), 7.81-7.91 (m, 4H),7.75 (d, J = 7.8 Hz, 1H), 7.48-7.56 (m, 2H), 7.41-7.48 (m, 1H),7.33-7.41 (m, 2H), 7.19-7.24 (m, 2H), 4.70 (s, 2H), 3.58-3.70 (m, 4H),2.22 (t, J = 7.0 Hz, 2H), 2.04 (d, J = 12.9 Hz, 2H), 1.62-1.79 (m, 2H),1.45 (dt, J = 14.8, 7.3 Hz, 2H), 1.21 (dq, J = 14.8, 7.3 Hz, 2H), 0.80(t, J = 7.4 Hz, 3H). 277

551.69 552.2; 1.41 min (Method H) 11.89 (br s, 2H), 7.76-7.87 (m, 4H),7.73 (d, J = 8.2 Hz, 1H), 7.47-7.55 (m, 2H), 7.40-7.47 (m, 1H),7.33-7.40 (m, 2H), 7.17-7.22 (m, 2H), 4.68 (s, 2H), 2.04-2.28 (m, 4H),1.71 (dd, J = 14.5, 7.8 Hz, 2H), 1.33-1.55 (m, 10H), 1.17 (dq, J = 15.0,7.4 Hz, 2H), 0.78 (t, J = 7.4 Hz, 3H). 278

551.69 552.1; 1.41 min (Method H) 11.91 (br s, 2H), 7.80-7.86 (m, 3H),7.77 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.47- 7.55 (m, 2H),7.39-7.46 (m, 1H), 7.32-7.38 (m, 2H), 7.15- 7.23 (m, 2H), 4.64 (s, 2H),2.18 (t, J = 7.0 Hz, 2H), 2.06 (d, J = 11.0 Hz, 2H), 1.38- 1.52 (m, 6H),1.31 (m, 3H), 1.12-1.25 (m, 2H), 0.72-0.86 (m, 6H). 279

571.68 572.1; 1.40 min. (Method H) 12.31 (br s, 2H), 7.77-7.85 (m, 3H),7.68-7.77 (m, 2H), 7.46- 7.55 (m, 2H), 7.38-7.46 (m, 1H), 7.27-7.36 (m,2H), 7.16- 7.23 (m, 2H), 7.07-7.16 (m, 4H), 4.60 (s, 2H), 3.62 (d, J =16.8 Hz, 2H), 3.13 (d, J = 17.2 Hz, 2H), 2.19 (t, J = 7.0 Hz, 2H), 1.45(dt, J = 14.8, 7.3 Hz, 2H), 1.12-1.27 (m, 2H), 0.79 (t, J = 7.2 Hz, 3H).

Example 280: Methyl1-(N-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylate

Intermediate 280a: (Z)-Methyl1-(N-((6′-(N′-hydroxycarbamimidoyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylate

To a solution of methyl1-(N-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentan-amido)cyclohexanecarboxylate(prepared from methyl 1-amino-4-cyclohexanecarboxylate according to themethod described for the synthesis of Intermediate 268d) (0.100 g, 0.197mmol) in ethanol (2 mL) was added hydroxylamine hydrochloride (0.137 g,1.97 mmol) and DIEA (0.342 mL, 1.97 mmol). The vessel was sealed and themixture was heated at 85° C. for 20 h. The cooled mixture was evaporatedand to the residue was dissolved in dimethyl sulfoxide (2.5 mL) andfiltered. The filtrate was submitted to purification by prep LC (MethodF, TFA as modifier) to afford the title compound as a white solid (0.074g, 0.113 mmol, 57% yield). LC-MS (Method H): 1.37 min, [M+H]⁺=542.2; ¹HNMR (DMSO-d₆) δ ppm 12.60 (br s, 1H), 11.15 (br s, 1H), 9.16 (br s, 1H),8.98 (br s, 2H), 7.87 (dd, J=8.0, 1.8 Hz, 1H), 7.78-7.85 (m, 3H), 7.70(d, J=8.2 Hz, 1H), 7.42-7.55 (m, 7H), 4.75 (s, 2H), 3.61 (s, 3H), 2.22(t, J=7.0 Hz, 2H), 1.95-2.11 (m, 2H), 1.32-1.62 (m, 9H), 1.05-1.28 (m,3H), 0.81 (t, J=7.2 Hz, 3H).

Example 280: Methyl1-(N-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylate

To a solution of Intermediate 280a (0.072 g, 0.110 mmol) in THF (5 mL)was added DBU (0.084 g, 0.549 mmol) and N,N′-carbonyldiimidazole (0.089g, 0.549 mmol) and the mixture was stirred at 50° C. for 2 h. The cooledmixture was evaporated and the residue was taken up in DMSO (2.5 mL) andtrifluoroacetic acid (0.100 mL) was added. The solution was submitted toprep LC (Method F, TFA as modifier) to afford the title compound (0.074g, 0.113 mmol, 57% yield) as a white solid. LC-MS (Method H): 1.46 min,[M+H]⁺=568.2; ¹H NMR (DMSO-d₆) δ ppm 12.41 (br s. 1H), 7.86 (dd, J=8.0,1.8 Hz, 1H), 7.82 (d, J=7.4 Hz, 2H), 7.79 (d, J=1.6 Hz, 1H), 7.75 (d,J=8.2 Hz, 1H), 7.39-7.56 (m, 7H), 4.73 (s, 2H), 3.59 (s, 3H), 2.22 (t,J=7.2 Hz, 2H), 2.03 (d, J=7.4 Hz, 2H), 1.33-1.63 (m, 9H), 1.03-1.29 (m,3H), 0.80 (t, J=7.4 Hz, 3H).

Example 281:1-(N-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

To a solution of Example 280 (0.025 g, 0.028 mmol) in DMSO (1 mL) wasadded 2.5M NaOH (0.225 mL, 0.564 mmol) and the mixture was stirred at75° C. for 18 h. To the cooled mixture was added trifluoroacetic acid(0.100 mL) and the solution was purified by prep LC (Method F, TFA asmodifier) to afford the title compound (0.009 g, 0.016 mmol, 57% yield)as a white solid. LC-MS (Method H): 1.39 min, [M+H]⁺=554.2; ¹H NMR(DMSO-d₆) δ ppm 12.41 (s, 1H), 7.72-7.89 (m, 5H), 7.47-7.55 (m, 4H),7.39-7.47 (m, 3H), 4.72 (s, 2H), 2.21 (t, J=7.0 Hz, 2H), 1.96-2.14 (m,2H), 1.32-1.71 (m, 9H), 1.00-1.28 (m, 3H), 0.79 (t, J=7.4 Hz, 3H).

Intermediate 282a: Methyl1-(N-(4-bromobenzyl)pentanamido)-4-oxocyclohexane-carboxylate

The title compound was prepared as an orange crystalline solid frommethyl 1-amino-4-oxocyclohexanecarboxylate, according to the methoddescribed for the synthesis of Intermediate 268b. LC-MS (Method H): 1.31min, [M+H]⁺=424.0; ¹H NMR (CDCl₃) δ ppm 7.50-7.56 (m, 2H), 7.29 (m, 2H),4.56 (s, 2H), 3.82 (s, 3H), 2.70 (ddd, J=16.0, 12.9, 6.3 Hz, 2H),2.48-2.62 (m, 2H), 2.22-2.33 (m, 4H), 1.87 (td, J=13.1, 5.5 Hz, 2H),1.55-1.68 (m, 2H), 1.22-1.36 (m, 2H), 0.88 (t, J=7.4 Hz, 3H).

Intermediate 282b: (1R,4R)-Methyl1-(N-(4-bromobenzyl)pentanamido)-4-hydroxycyclohexanecarboxylate

To an ice-cold mixture of Intermediate 282a (0.300 g, 0.707 mmol) inethanol (10 mL) was added sodium borohydride (0.080 g, 2.12 mmol) andthe resulting mixture was stirred for 30 min. The reaction mixture wasthen quenched with H₂O (2 mL) and 2M HCl (2 mL) and stirring wascontinued for 5 min. The resulting mixture was partitioned with H₂O (50mL) and tert-butylmethyl ether (50 mL) and the aqueous layer wasseparated and re-extracted with tert-butylmethyl ether (25 mL). Thecombined organic extract was dried over anhydrous sodium sulfate,filtered and evaporated. The residue was purified by flashchromatography (25 g ISCO-type column, eluting with 0 to 35%acetone/hexane) to give the title compound (0.280 g, 0.657 mmol, 93%yield) as a clear, colorless gum. LC-MS (Method H): 1.30 min,[M+H]⁺=426.0; ¹H NMR (CDCl₃) δ ppm 7.48-7.55 (m, 2H), 7.29 (d, J=8.6 Hz,2H), 4.53 (s, 2H), 3.77 (s, 3H), 3.46-3.57 (m, 1H), 2.30 (d, J=12.1 Hz,2H), 2.23 (t, J=7.2 Hz, 2H), 1.77-1.89 (m, 2H), 1.63-1.77 (m, 2H),1.52-1.63 (m, 2H), 1.46 (dt, J=13.3, 3.9 Hz, 3H), 1.19-1.33 (m, 2H),0.86 (t, J=7.4 Hz, 3H).

Intermediate 282c: (1R,4R)-Methyl1-(N-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-4-hydroxycyclohexanecarboxylate

Intermediate 282c was prepared from Intermediate 282b as an off whitesolid, according to the procedure described for the synthesis ofIntermediate 268d. LC-MS (Method H): 1.39 min, [M+H]⁺=525.2; ¹H NMR(DMSO-d₆) δ ppm 8.03 (d, J=8.2 Hz, 1H), 7.81-7.92 (m, 3H), 7.72 (d,J=8.2 Hz, 2H), 7.42-7.67 (m, 6H), 4.76 (s, 2H), 4.53 (d, J=4.3 Hz, 1H),3.62 (s, 3H), 3.34-3.47 (m, 1H), 2.23 (t, J=7.0 Hz, 2H), 2.04 (d, J=11.3Hz, 2H), 1.54-1.67 (m, 3H), 1.39-1.54 (m, 3H), 1.09-1.36 (m, 4H),0.77-0.82 (m, 2H).

Example 283:(1R,4R)-1-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-pentanamido)-4-hydroxycyclohexanecarboxylicacid

Intermediate 283a: (1R,4R)-Methyl1-(N-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-4-hydroxycyclohexanecarboxylate

To a vial containing Intermediate 282c (0.080 g, 0.152 mmol) in toluene(3 mL) was added azidotrimethylsilane (0.161 mL, 1.22 mmol) anddibutyltin oxide (0.038 g, 0.152 mmol). The reaction vessel was sealedand the mixture was heated at 110° C. for 18 h. The cooled mixture wasevaporated and the residue was taken up in a mixture of DMSO (2.5 mL)and trifluoroacetic acid (0.100 mL). Purification by prep LC (Method F,TFA as modifier) afforded the title compound (0.050 g, 0.088 mmol, 57%yield) as a white solid. LC-MS (Method H): 1.31 min, [M−H]=566.2.

Example 283:(1R,4R)-1-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentan-amido)-4-hydroxycyclohexanecarboxylicacid

To a solution of Intermediate 283a (0.030 g, 0.053 mmol) in THF (3 mL)was added potassium trimethylsilanolate (0.068 g, 0.528 mmol) and themixture was stirred at RT for 18 h. Formic acid (0.100 mL) was thenadded, the volatiles were evaporated and the residue was dissolved inDMSO (3 mL). Purification by prep LC (Method F, TFA as modifier)afforded the title compound (0.008 g, 0.014 mmol, 27% yield) as a whitesolid. LC-MS (Method H): 1.30 min, [M−H]=554.2; ¹H NMR (15% v/vacetone-d₆/CDCl₃) δ ppm 7.76 (d, J=7.8 Hz, 1H), 7.49-7.64 (m, 3H),7.30-7.38 (m, 2H), 7.20-7.30 (m, 4H), 7.09 (d, J=7.0 Hz, 2H), 4.49 (s,1H), 3.32-3.46 (m, 1H), 2.07-2.28 (m, 3H), 1.98 (d quint, J=4.3, 2.2 Hz,4H), 1.66 (m, 3H), 1.28-1.52 (m, 3H), 1.06-1.20 (m, 2H), 0.70 (t, J=7.4Hz, 3H).

Example 284:(1S,4S)-1-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-4-hydroxycyclohexanecarboxylicacid

Intermediate 284a:1-(N-(4-Bromobenzyl)pentanamido)-4-oxocyclohexanecarboxylic acid

A solution of Intermediate 282a (0.300 g, 0.707 mmol) in DCM (10 mL) wascooled at 0° C. and iodotrimethylsilane (0.300 mL, 2.12 ml) was added inone portion. The mixture was then allowed to warm to RT with stirringfor 2 h. This mixture was then added to a well-stirred mixture of ACN(10 mL) and 1M HCl and stirring was continued for 30 min. The volatileswere then evaporated and the residue was taken up in DMSO (10 mL) andformic acid (0.200 mL) was added. Purification by prep LC (Method F,formic acid as modifier) afforded the title compound (0.251 g, 0.621mmol, 87% yield) as a white solid. LC-MS (Method H): 1.29 min,[M−H]=410.1.

Intermediate 284b:1-(N-((6′-Cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-4-oxocyclohexanecarboxylicacid

The title compound was prepared from Intermediate 284a, according to themethod described for the synthesis of Intermediate 268d, and wasisolated as an off-white solid. LC-MS (Method H): 1.39 min,[M+H]⁺=509.2; ¹H NMR (DMSO-d₆) δ ppm 12.49 (br s, 1H), 8.03 (d, J=7.8Hz, 1H), 7.80-7.92 (m, 4H), 7.72 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz,2H), 7.41-7.56 (m, 3H), 4.82 (s, 2H), 2.43-2.57 (m, 2H), 2.15-2.36 (m,6H), 1.96-2.15 (m, 2H), 1.48 (quint, J=7.3 Hz, 2H), 1.23 (dq, J=15.0,7.4 Hz, 2H), 0.80 (t, J=7.4 Hz, 3H).

Intermediate 284c:1-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-4-oxocyclohexanecarboxylicacid

The title compound was prepared from Intermediate 284b according to themethod described for the synthesis of Intermediate 283a and was isolatedas an off-white solid. LC-MS (Method H): 1.32 min, [M+H]⁺=552.2; ¹H NMR(CDCl₃) δ ppm 8.03 (d, J=8.2 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H), 7.53-7.64(m, 3H), 7.36-7.47 (m, 3H), 7.28-7.34 (m, 2H), 7.00-7.10 (m, 2H), 4.65(br s, 2H), 2.79 (m, 2H), 2.53 (m, 2H), 2.22-2.44 (m, 4H), 1.96 (dd,J=12.3, 8.0 Hz, 2H), 1.62 (dt, J=15.2, 7.5 Hz, 2H), 1.20-1.37 (m, 2H),0.85 (t, J=7.4 Hz, 3H).

Example 284:(1S,4S)-1-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-4-hydroxycyclohexanecarboxylicacid

A solution of Intermediate 284c (0.030 g, 0.054 mmol) in dry THF (6 mL)was cooled at −78° C. under N₂. To this mixture was added a solution ofL-Selectride (1M in THF, 0.272 mL, 0.272 mmol) and stirring wascontinued at the same temperature for 30 min. The reaction was quenchedby the addition of AcOH (0.100 mL) and the reaction was allowed to warmto RT. The volatiles were then removed under reduced pressure and theresidue was taken up in DMSO (2 mL). This solution was submitted topurification by prep LC (Method F, formic acid as modifier) to affordthe title compound (0.021 g, 0.038 mmol, 69% yield) as a white solid.LC-MS (Method H): 1.29 min, [M−H]=554.1. ¹H NMR (DMSO-d₆) δ ppm 11.97(br s, 2H), 7.76-7.86 (m, 3H), 7.67-7.76 (m, 2H), 7.46-7.55 (m, 2H),7.30-7.46 (m, 3H), 7.20 (dd, J=8.2, 2.7 Hz, 2H), 4.63 (d, J=7.0 Hz, 2H),4.49 (br s, 0.5H), 3.73 (br s, 0.5H), 2.11-2.25 (m, 2H), 1.95-2.11 (m,1H), 1.67-1.90 (m, 2H), 1.38-1.67 (m, 7H), 1.08-1.32 (m, 2H), 0.79 (t,J=7.4 Hz, 3H).

Example 285:1-(N-((5′-Phenoxy-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

Intermediate 285a: Methyl1-(N-(4-bromobenzyl)pentanamido)cyclohexanecarboxylate

The title compound was prepared from methyl1-amino-cyclohexanecarboxylate according to the method described for thesynthesis of Intermediate 268b and was isolated as an orange crystallinesolid. LC-MS (Method H): 1.43 min, [M+H]⁺=410.0; ¹H NMR (DMSO-d₆) δ ppm7.50-7.64 (m, 2H), 7.27-7.42 (m, 2H), 4.64 (s, 2H), 3.58 (s, 3H), 2.17(t, J=7.0 Hz, 2H), 1.97 (d, J=10.2 Hz, 2H), 1.32-1.61 (m, 8H), 1.17 (dt,J=14.9, 7.4 Hz, 4H), 0.78 (t, J=7.2 Hz, 3H).

Intermediate 285b: Methyl1-(N-((2′-cyano-5′-fluoro-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylate

The title compound was prepared by the reaction Intermediate 285a (0.500g, 1.22 mmol) with4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(0.602 g, 2.44 mmol), according to the method described for thesynthesis of Intermediate 330b, to give a white solid (0.472 g, 1.05mmol, 86% yield). HRMS (ESI): Calcd for C₂₇H₃₂FN₂O₃ [M+H]⁺ m/z 451.2391;found 451.2416. ¹H NMR (CDCl₃) δ ppm 7.79 (dd, J=8.6, 5.5 Hz, 1H),7.52-7.62 (m, 4H), 7.23-7.27 (m, 1H), 7.17 (td, J=8.2, 2.7 Hz, 1H), 4.69(s, 2H), 3.78 (s, 3H), 2.18-2.35 (m, 4H), 1.51-1.80 (m, 8H), 1.43 (td,J=12.8, 4.1 Hz, 2H), 1.29 (dq, J=15.2, 7.5 Hz, 2H), 0.87 (t, J=7.2 Hz,3H).

Intermediate 285c:1-(N-((2′-Cyano-5′-fluoro-[1,1′-biphenyl]-4-yl)methyl)pentan-amido)cyclohexanecarboxylicacid

The title compound was prepared from Intermediate 285b according to themethod described for the synthesis of Intermediate 284a and was isolatedas an off white solid. LC-MS (Method H): 1.37 min, [M−H]=435.1; ¹H NMR(DMSO-d₆) δ ppm 12.01 (br s, 1H), 8.06 (dd, J=8.6, 5.5 Hz, 1H),7.54-7.68 (m, 5H), 7.46 (td, J=8.4, 2.7 Hz, 1H), 4.75 (s, 2H), 2.21 (t,J=7.0 Hz, 2H), 2.06 (d, J=11.3 Hz, 2H), 1.35-1.61 (m, 8H), 1.02-1.27 (m,4H), 0.79 (t, J=7.2 Hz, 3H).

Intermediate 285d:1-(N-((2′-Cyano-5′-phenoxy-[1,1′-biphenyl]-4-yl)methyl)pentan-amido)cyclohexanecarboxylicacid

The title compound was prepared from Intermediate 285c, according to themethod described for the synthesis of Intermediate 330c and was isolatedas an off-white solid. LC-MS (Method H): 1.37 min, [M−H]=509.1; ¹H NMR(DMSO-d₆) δ ppm 11.98 (br s, 1H), 7.93 (d, J=8.6 Hz, 1H), 7.52-7.62 (m,4H), 7.44-7.52 (m, 2H), 7.24-7.32 (m, 1H), 7.16-7.24 (m, 2H), 7.13 (d,J=2.7 Hz, 1H), 7.06 (dd, J=8.6, 2.3 Hz, 1H), 4.73 (s, 2H), 2.19 (t,J=7.0 Hz, 2H), 2.05 (d, J=11.7 Hz, 2H), 1.34-1.60 (m, 9H), 1.01-1.27 (m,3H), 0.77 (t, J=7.4 Hz, 3H).

Example 285:1-(N-((5′-Phenoxy-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

The title compound was prepared from Intermediate 285d, according to themethod described for the synthesis of Intermediate 283a and was isolatedas an off-white solid. LC-MS (Method H): 1.60 min, [M−H]=552.1; ¹H NMR(DMSO-d₆) δ ppm 11.91 (br s, 2H), 7.65 (d, J=8.6 Hz, 1H), 7.40-7.52 (m,2H), 7.28-7.38 (m, 2H), 7.21-7.26 (m, 1H), 7.16-7.21 (m, 2H), 7.09-7.15(m, 2H), 7.04-7.09 (m, 2H), 4.63 (s, 2H), 2.14 (t, J=7.0 Hz, 2H), 2.01(d, J=11.7 Hz, 2H), 1.34-1.64 (m, 9H), 0.98-1.24 (m, 3H), 0.76 (t, J=7.4Hz, 3H).

The following examples were similarly prepared from the appropriatephenol or hydroxypyridine, as described for the synthesis of Example 285above. Analytical LC-MS injections were used to determine the finalpurity and the retention time is reported for each compound and themethod used is referred to as Method A1, Method A2 or Method H.

LC-MS m/z [M + H]⁺; ¹H NMR (400 MHz, Ex Structure MW RT (Method)DMSO-d₆) δ ppm 286

554.65 555.2; 1.29 min (Method H) 11.91 (br s, 2H), 8.53 (d, J = 2.7 Hz,1H), 8.45 (dd, J = 4.7, 1.2 Hz, 1H), 7.58-7.73 (m, 2H), 7.50 (dd, J =8.2, 4.7 Hz, 1H), 7.28-7.40 (m, 2H), 7.14-7.25 (m, 2H), 7.02- 7.14 (m,2H), 4.63 (s, 2H), 2.14 (t, J = 7.0 Hz, 2H), 2.01 (d, J = 11.3 Hz, 2H),1.30- 1.68 (m, 6H), 1.03-1.22 (m, 3H), 0.77 (t, J = 7.2 Hz, 3H). 287

637.66 638.1; 1.47 min (Method H) 11.92 (br s, 2H), 7.70 (d, J = 8.2 Hz,1H), 7.54-7.62 (m, 1H), 7.31-7.38 (m, 2H), 7.16-7.26 (m, 5H), 7.04- 7.11(m, 2H), 4.63 (s, 2H), 2.14 (t, J = 7.2 Hz, 2H), 2.02 (d, J = 12.1Hz,2H), 1.31-1.67 (m, 9H), 1.00- 1.22 (m, 3H), 0.77 (t, J = 7.2 Hz, 3H).

Example 288:1-(N-((5′-(1-Methyl-1H-pyrazol-4-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

Intermediate 288a: Methyl1-(N-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylate

The title compound was prepared by the reaction of Intermediate 285a0.800 g, 1.95 mmol) with4-chloro-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile (0.973 g,3.90 mmol), according to the method described for the synthesis ofIntermediate 330b and was isolated as a white solid (0.440 g, 0.942mmol, 48% yield). HRMS (ESI): Calcd for C₂₇H₃₂ClN₂O₃ [M+H]⁺ m/z467.2096; found 467.2110. ¹H NMR (CDCl₃) δ ppm 7.72 (d, J=8.2 Hz, 1H),7.58 (m, 4H), 7.55 (d, J=2.0 Hz, 1H), 7.45 (dd, J=8.4, 2.2 Hz, 1H), 4.69(s, 2H), 3.78 (s, 3H), 2.21-2.33 (m, 4H), 1.51-1.77 (m, 8H), 1.43 (td,J=12.7, 4.3 Hz, 2H), 1.23-1.36 (m, 2H), 0.87 (t, J=7.2 Hz, 3H).

Intermediate 288b:1-(N-((5′-Chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)pentan-amido)cyclohexanecarboxylicacid

The title compound was prepared from Intermediate 288a according to themethod described for the synthesis of Intermediate 284a and was isolatedas an off white solid. LC-MS (Method H): 1.37 min, [M−H]=451.0; ¹H NMR(DMSO-d₆) δ ppm 11.99 (br s, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.76 (d, J=2.0Hz, 1H), 7.53-7.71 (m, 5H), 4.76 (s, 2H), 2.21 (t, J=7.0 Hz, 2H), 2.06(d, J=11.3 Hz, 2H), 1.30-1.61 (m, 9H), 1.01-1.30 (m, 3H), 0.79 (t, J=7.2Hz, 3H).

Intermediate 288c:1-(N-((2′-Cyano-5′-(1-methyl-1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

To a solution of Intermediate 288b (0.044 g, 0.088 mmol) in 10% v/vethanol/toluene (3 mL) was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.055 g, 0.265 mmol) and 2M potassium phosphate (0.066 mL, 0.132 mmol).This stirred mixture was purged with a stream of N₂ for 15 min.Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.006 g, 0.0088 mmol) was then added and the mixture stirred at 100° C.for 3 h. The cooled reaction mixture was evaporated, the residue wastaken up in DMSO (3.5 mL) and the mixture was filtered and the filtratepurified by prep LC (Method F, formic acid as modifier) to afford thetitle compound as a white solid (0.037 g, 0.074 mmol, 84% yield). LC-MS(Method H): 1.29 min, [M−H]=497.1; HRMS (ESI): Calcd for C₃₀H₃₅N₄O₃[M+H]⁺ m/z 499.2704; found 499.2707.

Example 288:1-(N-((5′-(1-Methyl-1H-pyrazol-4-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

The title compound was prepared from Intermediate 288c according to themethod described for the synthesis of Intermediate 283a and was isolatedas a white solid. LC-MS (Method H): 1.26 min, [M−H]=540.1; ¹H NMR(DMSO-d₆) δ ppm 11.48 (s, 2H), 8.36 (s, 1H), 8.05 (s, 1H), 7.70-7.79 (m,2H), 7.62 (d, J=8.6 Hz, 1H), 7.31-7.42 (m, 2H), 7.08-7.19 (m, 2H), 4.66(s, 2H), 3.88 (s, 3H), 2.18 (t, J=7.0 Hz, 2H), 2.04 (d, J=12.1 Hz, 2H),1.34-1.75 (m, 9H), 1.12-1.27 (m, 3H), 0.80 (t, J=7.2 Hz, 3H).

The following examples were similarly prepared from the appropriateboronic acids or boronate esters, as described for the synthesis ofExample 288 above. Analytical LC-MS injections were used to determinethe final purity, the retention time is reported for each compound andthe method used is referred to as Method A1, Method A2 or Method H.

LC-MS m/z [M − H]⁻; ¹H NMR (400 MHz, Ex Structure MW RT (Method)DMSO-d₆) δ ppm 289

573.64 572.0; 1.41 min (Method H) 11.92 (br s, 2H), 7.91-7.96 (m, 1H),7.90 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.62- 7.72 (m, 2H),7.35-7.41 (m, 2H), 7.31 (tt, J = 9.3, 2.2 Hz, 1H), 7.17-7.24 (m, 2H),4.66 (s, 2H), 2.18 (t, J = 7.0 Hz, 2H), 2.04 (d, J = 11.7 Hz, 2H),1.32-1.72 (m, 9H), 1.00-1.30 (m, 3H), 0.79 (t, J = 7.4 Hz, 3H). 290

568.67 567.2; 1.33 min (Method H) 11.92 (s, 2H), 8.24 (dd, J = 5.1, 2.0Hz, 1H), 7.94 (dd, J = 7.2, 1.8 Hz, 1H), 7.73- 7.78 (m, 1H), 7.66-7.73(m, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.10-7.19 (m, 3H), 4.65 (s, 2H), 3.92(s, 3H), 2.17 (t, J = 7.0 Hz, 2H), 2.03 (d, J = 12.1 Hz, 2H), 1.30-1.73(m, 9H), 1.01-1.30 (m, 3H), 0.78 (t, J = 7.2 Hz, 3H). 291

594.71 593.1; 1.28 min (Method H) 11.92 (br s, 2H), 10.08 (s, 1H),7.81-7.86 (m, 1H), 7.80- 7.81 (m, 1H), 7.76-7.80 (m, 2H), 7.67-7.75 (m,3H), 7.32- 7.42 (m, 2H), 7.12-7.24 (m, 2H), 4.66 (s, 2H), 2.18 (t, J =7.2 Hz, 2H), 2.07 (s, 3H), 2.03 (d, J = 12.1 Hz, 2H), 1.32-1.73 (m, 9H),1.02-1.32 (m, 3H), 0.79 (t, J = 7.2 Hz, 3H). 292

587.2; 1.340 min. (Method H) 11.94 (br s, 2H), 8.94 (dd, J = 4.3, 1.6Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 7.4 Hz, 1H), 8.27 (dd, J= 9.0, 2.0 Hz, 1H), 8.14 (d, J = 8.6 Hz, 1H), 8.03 (dd, J = 7.8, 1.6 Hz,1H), 7.99 (s, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.59 (dd, J = 8.2, 3.9 Hz,1H), 7.35-7.45 (m, 2H), 7.18-7.29 (m, 2H), 4.67 (s, 2H), 2.19 (t, J =7.0 Hz, 2H), 2.03 (d, J = 12.1 Hz, 2H), 1.36-1.71 (m, 9H), 1.04- 1.33(m, 3H), 0.80 (t, J = 7.4 Hz, 3H).

Example 293:1-(N-((5′-(Pyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

Intermediate 293a: Methyl1-(N-((2′-cyano-5′-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylate

In a 20 mL pressure vial containing Intermediate 288a (0.700 g, 1.50mmol) and 5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane (1.016 g,4.50 mmol) was added 1,4-dioxane (15 mL), KOAc (0.446 g, 4.50 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.236 g, 0.300 mmol). The stirred mixture was purged with a streamof N₂ for 15 min and then it was heated at 85° C. for 1.5 h. The cooledmixture was partitioned with H₂O (25 mL) and EtOAc (50 mL) and theorganic phase was separated, dried over anhydrous sodium sulfate,filtered and evaporated. The residue was purified by flashchromatography using a 12 g ISCO-type column and eluting with 20 to 50%EtOAc/hexane to give the title compound (0.620 g, 1.14 mmol, 76% yield)as a yellow foam. ¹H NMR (CDCl₃) δ ppm 7.95 (s, 1H), 7.85 (dd, J=7.6,1.0 Hz, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.59-7.63 (m, 2H), 7.50-7.55 (m,2H), 4.68 (s, 2H), 3.80 (s, 4H), 3.78 (s, 3H), 2.29 (m, 4H), 1.57-1.76(m, 7H), 1.43 (td, J=12.9, 3.9 Hz, 2H), 1.25-1.34 (m, 3H), 1.04 (s, 6H),0.88 (t, J=7.4 Hz, 3H).

Intermediate 293b: Methyl1-(N-((2′-cyano-5′-(pyridin-2-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylate

To a mixture of Intermediate 293a (0.075 g, 0.138 mmol) in 20% v/vethanol/toluene (3 mL) was added 2-bromopyridine (0.039 mL, 0.413 mmol)and 2M potassium phosphate (0.138 mL, 0.275 mmol). This stirred mixturewas purged with a stream of N₂ for 15 min and thenchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.011 g, 0.014 mmol) was added and the mixture was stirred at 100° C.for 2 h. The cooled reaction mixture was evaporated and the residue wastaken up in DMSO (3.5 mL). Purification by prep LC (Method F, formicacid as modifier) afforded the title compound (26 mg, 0.051 mmol, 37%yield) as a white solid. LC-MS (Method H): 1.40 min, [M+H]⁺=510.2; HRMS(ESI): Calcd for C₃₂H₃₆N₃O₃ [M+H]⁺ m/z 510.2751; found 510.2765.

Intermediate 293c:1-(N-((2′-Cyano-5′-(pyridin-2-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

The title compound was prepared from Intermediate 293b according to themethod described for the synthesis of Intermediate 284a and was isolatedas an off-white solid. LC-MS (Method H): 1.37 min, [M+H]⁺=496.2; HRMS(ESI): Calcd for C₃₁H₃₄N₃O₃ [M+H]⁺ m/z 496.2596; found 496.2606.

Example 293:1-(N-((5′-(pyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

The title compound was prepared from Intermediate 293c according to themethod described for the synthesis of Intermediate 283a and was isolatedas an off-white solid. LC-MS (Method H): 1.30 min, [M+H]⁺=539.2; ¹H NMR(DMSO-d₆) δ ppm 11.93 (s, 2H), 8.73 (d, J=4.7 Hz, 1H), 8.23-8.30 (m,2H), 8.18 (d, J=7.8 Hz, 1H), 7.95 (td, J=7.8, 1.6 Hz, 1H), 7.79 (d,J=7.8 Hz, 1H), 7.44 (dd, J=7.4, 4.7 Hz, 1H), 7.39 (d, J=8.2 Hz, 2H),7.18 (d, J=8.2 Hz, 2H), 4.67 (s, 2H), 2.19 (t, J=7.0 Hz, 2H), 2.05 (d,J=11.7 Hz, 2H), 1.37-1.67 (m, 9H), 1.07-1.25 (m, 3H), 0.80 (t, J=7.2 Hz,3H).

The following examples were similarly prepared from the corresponding2-bromopyridine or 2-chloropyridine, as described for the synthesis ofExample 293 above. Analytical LC-MS injections were used to determinethe final purity, the retention time is reported for each compound andthe method used is referred to as Method A1, Method A2 or Method H.

LC-MS m/z [M + H]⁺; ¹H NMR (400 MHz, Ex Structure MW RT (Method)DMSO-d₆) δ ppm 294

552.68 553.3; 1.33 min (Method H) 11.94 (s, 2H), 8.16-8.25 (m, 2H), 7.94(d, J = 7.0 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H),7.43 (br s, 2H), 7.29 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 7.8 Hz, 2H),4.67 (br s, 2H), 2.56 (s, 3H), 2.02-2.25 (m, 4H), 1.36-1.64 (m, 9H),1.09-1.25 (m, 3H), 0.79 (t, J = 7.2 Hz, 3H). 295

552.68 553.3; 1.32 min (Method H) 11.93 (s, 2H), 8.59 (d, J = 5.1 Hz,1H), 8.27 (dd, J = 8.0, 1.8 Hz, 1H), 8.22-8.25 (m, 1H), 8.09 (s, 1H),7.79 (d, J = 8.2 Hz, 1H), 7.37-7.42 (m, 2H), 7.32 (d, J = 4.7 Hz, 1H),7.16-7.21 (m, 2H), 4.67 (s, 2H), 2.44 (s, 3H), 2.19 (t, J = 7.2 Hz, 2H),2.04 (d, J = 11.3 Hz, 2H), 1.36-1.69 (m, 9H), 1.12-1.26 (m, 3H),0.77-0.83 (m, 3H). 296

568.68 569.2; 1.39 min (Method H) 11.91 (s, 2H), 8.26 (dd, J = 8.0, 1.8Hz, 1H), 8.17-8.23 (m, 1H), 7.79-7.86 (m, 1H), 7.76 (d, J = 7.4 Hz, 2H),7.33-7.42 (m, 2H), 7.12-7.20 (m, 2H), 6.85 (d, J = 7.8 Hz, 1H), 4.65 (s,2H), 3.95 (s, 3H), 2.16 (t, J = 7.0 Hz, 2H), 1.96-2.09 (m, 2H),1.35-1.65 (m, 9H), 1.02-1.23 (m, 3H), 0.77 (t, J = 7.4 Hz, 3H).

Example 297:1-(N-((5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

Intermediate 297a: Methyl1-(N-((2′-cyano-5′-(3-methylpiperidin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylate

To a solution of Intermediate 288a (0.077 g, 0.165 mmol) in dry THF (3mL) were added 3-methylpiperidine (0.055 mL, 0.495 mmol), sodium2-methylpropan-2-olate (0.095 g, 0.989 mmol) andchloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (0.013 g, 0.016 mmol) and the mixture was stirred at 65° C. for 3h. The cooled mixture was then evaporated and the residue was taken upin DMSO (3.5 mL) and purified by prep LC (Method F, formic acid asmodifier) to afford the title compound as a white solid (0.050 g, 0.094mmol, 57% yield). LC-MS (Method H): 1.59 min, [M+H]⁺=530.3; HRMS (ESI):Calcd for C₃₃H₄₄N₃O₃ [M+H]⁺ m/z 530.3377; found 530.3389.

Intermediate 297b:1-(N-((2′-Cyano-5′-(3-methylpiperidin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

The title compound was prepared from Intermediate 297a according to themethod described for the synthesis of Intermediate 284a and was isolatedas an off-white solid.

LC-MS (Method H): 1.52 min, [M+H]⁺=516.3; HRMS (ESI): Calcd forC₃₂H₄₂N₃O₃ [M+H]⁺ m/z 516.3221; found 516.3242.

Example 297:1-(N-((5′-(3-Methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)cyclohexanecarboxylicacid

The title compound was prepared from Intermediate 297b according to themethod described for the synthesis of Intermediate 283a and was isolatedas an off-white solid. LC-MS (Method H): 1.41 min, [M+H]⁺=559.2; ¹H NMR(DMSO-d₆) δ ppm 11.92 (br s, 2H), 7.43 (d, J=8.6 Hz, 1H), 7.34 (d, J=8.2Hz, 2H), 7.04-7.12 (m, 3H), 6.94 (d, J=2.3 Hz, 1H), 4.64 (s, 2H),3.75-3.90 (m, 2H), 2.75 (td, J=12.1, 2.3 Hz, 1H), 2.44 (d, J=12.1 Hz,1H), 2.17 (t, J=7.0 Hz, 2H), 2.04 (d, J=12.1 Hz, 2H), 1.38-1.77 (m,13H), 1.02-1.25 (m, 4H), 0.92 (d, J=6.7 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H).

Example 298:4-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentan-amido)-1-phenylpiperidine-4-carboxylicacid

Intermediate 298a: 8-Phenyl-1,3,8-triazaspiro[4.5]decane-2,4-dione

To a solution of 1-phenylpiperidin-4-one (2.53 g, 14.46 mmol) in ethanol(75 mL) and H₂O (25 mL) was added ammonium carbonate (12.9 g, 134.3mmol) and potassium cyanide (2.11 g, 32.5 mmol.). The reaction vesselwas sealed and the mixture was then heated at 80-90° C. for 18 h. Thecooled mixture was concentrated in vacuo, H₂O (200 mL) was added to theresidue and the resulting suspension was briefly stirred at RT. Thismixture was then filtered and the residue washed with H₂O to give thetitle compound as a wet solid (ca. 3 g). The aqueous filtrate andwashings were combined and extracted with EtOAc (3×100 mL) and thecombined organic extract was washed (H₂O), dried. (anhydrous sodiumsulfate), filtered and evaporated to provide more of the title compoundas an impure solid (ca. 2 g). The combined solids thus obtained weretaken up in ethanol (200 mL) and the volatiles were removed underreduced pressure to give a brown solid. This solid was triturated amixture of 20% v/v of ethanol/tert-butylmethyl ether (50 mL) and theresulting suspension was filtered and the filter-cake was washed withCert-butylmethyl ether. The solid thus obtained was air-dried to givethe title compound (3.06 g, 12.5 mmol, 86% yield) as a brown solid whichwas used as such without further purification. ¹H NMR (DMSO-d₆) δ ppm10.67 (br s, 1H), 8.53 (s, 1H), 7.21 (dd, J=8.6, 7.4 Hz, 2H), 6.95 (d,J=8.2 Hz, 2H), 6.76 (t, J=7.2 Hz, 1H), 3.63 (dt, J=13.0, 3.9 Hz, 2H),2.99-3.16 (m, 2H), 1.81-1.97 (m, 2H), 1.60 (d, J=13.3 Hz, 2H).

Intermediate 298b: 4-amino-1-phenylpiperidine-4-carboxylic acid

A mixture of Intermediate 298a (3.06 g, 12.5 mmol) and 6M NaOH (100 mL,600 mmol) were heated at 100° C. in a sealed pressure bottle for 22 h.The reaction temperature was then increased to 130° C. and stirring wascontinued for 24 h. The cooled mixture was neutralized (pH 6-7) by theslow addition of AcOH to give a beige precipitate. The resultingsuspension was filtered and the filter-cake was washed with numeroussmall quantities of H₂O and then air-dried to give the title compound asa beige solid (2.64 g, 11.9 mmol, 96% yield). LC-MS (Method H): 0.34min, [M+H]⁺=221.1; HRMS (ESI): Calcd for C₁₂H₁₇N₂O₂ [M+H]⁺ m/z 221.1285;found 221.1284.

Intermediate 298c: Methyl 4-amino-1-phenylpiperidine-4-carboxylate

To a suspension of Intermediate 298b (2.64 g, 11.9 mmol) in MeOH (60 mL)was slowly added thionyl chloride (2.61 mL, 36.0 mmol) and then themixture was stirred at 65° C. for 18 h. The cooled mixture was thenevaporated under reduced pressure and the residue was taken up in H₂O(100 mL). This mixture was neutralized by the addition of 1M NaOH togive an off-white precipitate which was filtered and the filter-cake waswashed with several small portions of wate. The resulting solid wasair-dried to afford the title compound as an off-white solid (1.00 g,4.27 nmol, 35% yield). LC-MS (Method H): 0.88 min, [M+H]⁺=235.2; ¹H NMR(CDCl₃) δ ppm 7.19-7.33 (m, 2H), 6.91-7.00 (m, 2H), 6.79-6.89 (m, 1H),3.75 (s, 3H), 3.24-3.37 (m, 4H), 2.23 (ddd, J=13.5, 8.2, 5.7 Hz, 2H),1.62-1.73 (m, 2H), 1.56 (br s, 2H).

Intermediate 298d: Methyl4-((4-bromobenzyl)amino)-1-phenylpiperidine-4-carboxylate

To a mixture of Intermediate 298c (1.00 g, 4.27 mmol) in ACN (15 mL) wasadded 1-bromo-4-(bromomethyl)benzene (1.17 g, 4.69 mmol) and DIEA (0.97mL, 5.55 mmol), the vessel was sealed and the mixture was heated at 80°C. for 18 h. The cooled mixture was then evaporated under reducedpressure, the residue was taken up in tert-butylmethyl ether (100 mL)and saturated aqueous NaHCO₃ (25 mL) was added. The organic phase wasseparated and the aqueous phase was re-extracted with a further portionof tert-butylmethyl ether (20 mL). The combined organic extract wasdried over anhydrous sodium sulfate, filtered and evaporated. Theresidue obtained was purified by flash chromatography using a 25 gISCO-type column and eluting with a 0 to 10% acetone/hexane to give thetitle compound as a clear light yellow oil (1.60 g, 3.97 mmol, 93%yield). LC-MS (Method H): 1.28 min, [M+H]⁺=403.0. ¹H NMR (CDCl₃) δ ppm7.40-7.48 (m, 2H), 7.19-7.30 (m, 4H), 6.92-6.99 (m, 2H), 6.85 (t, J=7.2Hz, 1H), 3.77 (s, 3H), 3.59 (s, 2H), 3.32-3.41 (m, 2H), 3.22-3.32 (m,2H), 2.20 (ddd, J=13.6, 9.5, 3.9 Hz, 2H), 1.81-1.93 (m, 2H).

Intermediate 298e: Methyl4-(N-(4-bromobenzyl)pentanamido)-1-phenylpiperidine-4-carboxylate

To a mixture of Intermediate 298d (1.55 g, 3.84 mmol) in toluene (50 mL)was added DIEA (1.43 mL, 7.69 mmol) and pentanoyl chloride (0.69 mL,5.76 mmol) and the resulting mixture was stirred at 65° C. for 18 h.Additional portions of DIEA (1.43 mL, 7.69 mmol) and pentanoyl chloride(0.69 mL, 5.76 mmol) were then added and the mixture was stirred at thesame temperature for 2 h. Additional portions of DIEA (1.43 mLl, 7.69mmol) and pentanoyl chloride (0.69 mL, 5.76 mmol) were then added andthe mixture was stirred at the same temperature for another 1 h. Thecooled mixture was washed sequentially with 10% w/v aqueous citric acid(50 mL) and saturated aqueous NaHCO₃ (50 mL), then dried over anhydroussodium sulfate, filtered and evaporated. The residue was purified byflash chromatography using a 40 g ISCO-type column with a 0 to 20%acetone/hexane gradient to afford the title compound as an orange gum(1.59 g, 3.26 mmol, 85% yield). LC-MS (Method H): 1.46 min,[M+H]⁺=487.1; ¹H NMR (CDCl₃) δ ppm 7.48-7.55 (m, 2H), 7.28-7.34 (m, 2H),7.19-7.26 (m, 2H), 6.79-6.90 (m, 3H), 4.59 (s, 2H), 3.79 (s, 3H), 3.50(d, J=12.1 Hz, 2H), 3.10 (td, J=12.3, 2.0 Hz, 2H), 2.30-2.38 (m, 2H),2.27 (t, J=7.2 Hz, 2H), 1.88 (td, J=12.7, 5.1 Hz, 2H), 1.50-1.68 (m,2H), 1.23-1.35 (m, 2H), 0.88 (t, J=7.2 Hz, 3H).

Intermediate 298f: Methyl4-(N-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentan-amido)-1-phenylpiperidine-4-carboxylate

The title compound was prepared by the reaction Intermediate 298e (0.078g, 0.160 mmol) with Intermediate 268c (0.070 g, 0.240 mmol), accordingto the method described for the synthesis of Intermediate 330b, and wasisolated as a white solid (0.090 g, 0.154 mmol, 96% yield).). LC-MS(Method H): 1.55 min, [M+H]⁺=586.2; 41 NMR (CDCl₃) δ ppm 7.86 (d, J=8.2Hz, 1H), 7.75 (d, J=2.0 Hz, 1H), 7.62-7.71 (m, 5H), 7.54-7.59 (m, 2H),7.44-7.53 (m, 3H), 7.23 (dd, J=8.6, 7.4 Hz, 2H), 6.89 (d, J=8.2 Hz, 2H),6.82 (t, J=7.2 Hz, 1H), 4.74 (s, 2H), 3.81 (s, 3H), 3.54 (d, J=12.5 Hz,2H), 3.13 (t, J=11.7 Hz, 2H), 2.41 (d, J=12.9 Hz, 2H), 2.35 (t, J=7.4Hz, 2H), 1.95 (td, J=12.6, 4.9 Hz, 2H), 1.60-1.70 (m, 2H), 1.23-1.39 (m,2H), 0.90 (t, J=7.4 Hz, 3H).

Intermediate 298 g:4-(N-((6′-Cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-1-phenylpiperidine-4-carboxylicacid

The title compound was prepared from Intermediate 298f according to themethod described for the synthesis of Intermediate 284a and was isolatedas an off-white solid. LC-MS (Method H): 1.49 min, [M+H]⁺=572.2; HRMS(ESI): Calcd for C₃₇H₃₈N₃O₃ [M+H]⁺ m/z 572.2908; found 572.2917.

Example 298:4-(N-((6′-(2H-Tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentan-amido)-1-phenylpiperidine-4-carboxylicacid

The title compound was prepared from Intermediate 298 g according to themethod described for the synthesis of Intermediate 283a and was isolatedas an off-white solid. LC-MS (Method H): 1.39 min, [M+H]⁺=615.2; ¹H NMR(DMSO-d₆) δ ppm 12.28 (s, 2H), 7.78-7.90 (m, 4H), 7.75 (d, J=7.8 Hz,1H), 7.48-7.55 (m, 2H), 7.41-7.48 (m, 1H), 7.35-7.41 (m, 2H), 7.13-7.25(m, 4H), 6.85-6.96 (m, 2H), 6.75 (t, J=7.0 Hz, 1H), 4.71 (s, 2H), 3.52(d, J=12.1 Hz, 2H), 3.02 (t, J=11.3 Hz, 2H), 2.16-2.30 (m, 4H), 1.85(dd, J=12.1, 8.6 Hz, 2H), 1.42-1.51 (m, 2H), 1.16-1.26 (m, 2H), 0.81 (t,J=7.4 Hz, 3H).

Example 299:2-ethoxy-1-((5′-(4-methylpyridin-2-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 299a: 2-chloro-4-(4-methylpyridin-2-yl)benzonitrile

To a solution of 2-bromo-4-methylpyridine (455 mg, 2.65 mmol) and(3-chloro-4-cyanophenyl)boronic acid (400 mg, 2.205 mmol) in 4:1toluene/EtOH (10 mL) was added K₃PO₄ (2 M, aq) (2.205 mL, 4.41 mmol)followed by PdCl₂(dppf) (161 mg, 0.221 mmol). The resulting mixture wassparged with N₂ for 2 min before being sealed and heated at 120° C. for45 min in the microwave. The reaction mixture was diluted with EtOAc,concentrated onto celite and purified by ISCO (0-100% EtOAc Hexanes) toafford the title compound (299a, 220 mg, 0.962 mmol, 43.6% yield).LC-MS: MS (ESI) m/z: 229.0 [M+H]⁺; ¹H NMR (500 MHz, CDCl₃) δ 8.61 (d,J=5.0 Hz, 1H), 8.22 (s, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz,1H), 7.61 (s, 1H), 7.19 (d, J=5.1 Hz, 1H), 2.48 (s, 3H).

Intermediate 299b: methyl1-((2′-cyano-5′-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

To a pressure-rated vial containing I-005 (200 mg, 0.458 mmol),Intermediate 299a (115 mg, 0.504 mmol) and second generation xphosprecatalyst (36.1 mg, 0.046 mmol) was added dioxane (2292 μl) followedby 2 M K₃PO₄ (2 M aq) (458 μl, 0.917 mmol). The reaction mixture wassparged with N₂ for 2 min before being sealed and heated at 85° C. for18 h. The reaction mixture was then concentrated onto celite andpurified by ISCO (0-100% EtOAc/Hexanes) to afford the title compound(159 mg, 0.316 mmol, 69.0% yield). LC-MS (Method A2): 0.88 min,[M+H]⁺=503.0.

Example 299:2-ethoxy-1-((5′-(4-methylpyridin-2-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid Intermediate 299b (78 mg, 0.155 mmol) was dissolved in1-butyl-3-methylimidazolium acetate (1.2 mL) along with hydroxylaminehydrochloride (270 mg, 3.88 mmol). The reaction mixture was sealed andallowed to stir at 65° C. for 24 h. The reaction mixture was dilutedwith H₂O and extracted with EtOAc 3×. The combined organics were washedwith brine, dried with sodium sulfate, filtered and concentrated. Thecrude residue was dissolved in 5 mL of THF and DBU (0.234 mL, 1.552mmol) was added followed by CDI (252 mg, 1.552 mmol). The reactionmixture was allowed to stir at RT for 30 minutes. The reaction mixturewas concentrated and then re-dissolved in MeOH (5 mL). 1M NaOH (3.10 mL,3.10 mmol) was added and the reaction mixture was allowed to stir at 65°C. for 3 h. The mixture was then acidified to pH 3-4 with 10% citricacid and extracted with EtOAc 3×. The combined organic layer was washedwith brine, dried with sodium sulfate, filtered and concentrated. Thecrude residue was purified by reverse phase HPLC (Xbridge Prep ShieldRP18, 15 min gradient of 20-100% B. A=H₂O/MeOH 10 mM NH₄OAc 90:10.B═H₂O/MeOH 10 mM NH₄OAc 10:90) to afford the title compound (Example299, 7.9 mg, 0.014 mmol, 9.30% yield). MS (ESI)+=548.3. ¹H NMR (500 MHz,DMSO-d₆) δ 8.53 (br d, J=4.9 Hz, 1H), 8.22 (br d, J=7.6 Hz, 1H), 8.09(br s, 1H), 7.96 (br s, 1H), 7.75 (d, J=7.9 Hz, 1H), 7.66 (br d, J=7.0Hz, 1H), 7.57 (br d, J=7.6 Hz, 1H), 7.31 (br d, J=7.3 Hz, 2H), 7.24 (brd, J=4.0 Hz, 1H), 7.18 (br s, 1H), 7.07 (br d, J=7.9 Hz, 2H), 5.73 (brs, 2H), 4.67-4.52 (m, J=6.7 Hz, 2H), 2.38 (s, 3H), 1.40 (br t, J=6.3 Hz,3H). LC-MS retention time (Method A4): 1.298 min

Example 300:2-ethoxy-1-(5′-(5-methylpyridin-2-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 300a: methyl1-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

Intermediate 300a was synthesized from I-005 and4-chloro-2-iodobenzonitrile using the procedure described for 299b togive the title compound (Intermediate 300a, 2.55 g, 5.6 mmol, 61%yield). LC-MS (Method A2): 1.02 min, [M+H]⁺=446.0. ¹H NMR (500 MHz,CDCl₃) δ 7.77 (dd, J=7.8, 1.0 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.60 (dd,J=7.8, 1.0 Hz, 1H), 7.49-7.39 (m, 4H), 7.21 (t, J=7.8 Hz, 1H), 7.14 (d,J=8.3 Hz, 2H), 5.73 (s, 2H), 4.70 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 1.51(t, J=7.2 Hz, 3H).

Intermediate 300b: methyl1-((2′-cyano-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

To a flask containing Intermediate 300a (2100 mg, 4.71 mmol),bis(pinacolato)diborane (2392 mg, 9.42 mmol) and Pd₂(dba)₃ (431 mg,0.471 mmol) was added dioxane (2.35E+04 μl) followed by KOAc (2311 mg,23.55 mmol) anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane (225mg, 0.471 mmol) (XPhos). The reaction mixture was evacuated andbackfilled with N₂ (3×) and heated at 100° C. for 120 minutes. Thereaction mixture was concentrated onto celite and purified by ISCO(0-60% EtOAc/DCM) to afford the title compound (Intermediate 300b, 2.2g, 3.44 mmol, 73.0% yield). LC-MS: MS (ESI) m/z: 538.1 (M+H)⁺. ¹H NMR(500 MHz, CDCl₃) δ 7.87 (s, 1H), 7.84 (dd, J=7.7, 0.8 Hz, 1H), 7.79-7.70(m, 2H), 7.59 (dd, J=7.8, 1.0 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 7.21 (t,J=7.8 Hz, 1H), 7.10 (d, J=8.3 Hz, 2H), 5.71 (s, 2H), 4.70 (d, J=7.2 Hz,2H), 3.79 (s, 3H), 1.52 (t, J=7.2 Hz, 3H), 1.36 (s, 12H).

Intermediate 300c: methyl1-((2′-cyano-5′-(5-methylpyridin-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

Intermediate 300b (128 mg, 0.200 mmol) was dissolved in 4:1 toluene/EtOH(2 mL) along with XPhos generation two pre-catalyst (31.5 mg, 0.040mmol), K₃PO₄ (2 M, aq) (0.300 mL, 0.600 mmol) and2-bromo-5-methylpyridine (68.8 mg, 0.400 mmol). The reaction mixture wasevacuated and backfilled with N₂ (3×) then allowed to stir at 65° C. for2 h. The reaction mixture was concentrated onto celite and purified byISCO (0-100% DCM/EtOAc) to afford the title compound (Intermediate 300c,68 mg, 0.135 mmol, 67.7% yield). LC-MS: MS (ESI) m/z: 503.0 (M+H)⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.56 (s, 1H), 8.10 (d, J=1.4 Hz, 1H), 8.07-8.00(m, 1H), 7.84 (d, J=8.3 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.69 (d, J=8.0Hz, 1H), 7.60 (br d, J=8.0 Hz, 2H), 7.56-7.50 (m, J=8.3 Hz, 2H), 7.21(t, J=7.8 Hz, 1H), 7.16-7.12 (m, J=8.3 Hz, 2H), 5.73 (s, 2H), 4.71 (d,J=6.9 Hz, 2H), 3.80 (s, 3H), 2.42 (s, 3H), 1.52 (t, J=7.0 Hz, 3H).

Example 300:2-ethoxy-1-(5′-(5-methylpyridin-2-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Example 300 was synthesized from Intermediate 300c according to the sameprocedure described for Example 299 to give the title compound (Example300, 2.9 mg, 5.30 μmol, 3.91% yield). MS (ESI) m/z [M+H]⁺=548.3. ¹H NMR(500 MHz, DMSO-d₆) δ 8.50 (br s, 1H), 8.09 (br d, J=8.2 Hz, 1H),8.02-7.90 (m, 2H), 7.70 (br d, J=7.0 Hz, 1H), 7.67 (br d, J=7.9 Hz, 1H),7.60 (br d, J=7.9 Hz, 1H), 7.49 (br d, J=7.6 Hz, 1H), 7.27 (br d, J=7.6Hz, 2H), 7.15 (br t, J=7.6 Hz, 1H), 7.02 (br d, J=7.6 Hz, 2H), 5.70 (brs, 2H), 4.59 (q, J=7.0 Hz, 2H), 2.34 (s, 3H), 1.41 (br t, J=7.0 Hz, 3H).LC-MS retention time (Method A4): 1.291 min

The examples in the following table were prepared from the appropriatepyridyl bromide according to the sequence described for Example 300.

LC-MS m/z [M +H]⁺; RT ¹H NMR (500 MHz, Ex Structure MW (Method A4)DMSO-d₆) δ ppm 301

563.57 564.3; 1.213 min. ¹H NMR (500 MHz, DMSO- d₆) 8.48 (d, J = 5.5 Hz,1H), 8.20 (br d, J = 8.2 Hz, 1H), 8.09 (s, 1H), 7.72 (d, J = 7.9 Hz,1H), 7.68-7.59 (m, 2H), 7.54 (br d, J = 7.9 Hz, 1H), 7.30 (br d, J = 7.6Hz, 2H), 7.18 (t, J = 7.8 Hz, 1H), 7.05 (br d, J = 7.9 Hz, 2H), 6.98 (d,J = 6.1 Hz, 1H), 5.69 (s, 2H), 4.60 (q, J = 7.0 Hz, 2H), 3.90 (s, 3H),1.40 (t, J = 7.0 Hz, 3H). 302

599.55 600.0; 1.615 min. ¹H NMR (500 MHz, DMSO- d₆) δ 8.67 (d, J = 5.6Hz, 1H), 8.19 (dd, J = 8.1, 1.4 Hz, 1H), 8.13-8.03 (m, 1H), 7.92-7.80(m, 1H), 7.77-7.68 (m, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.58- 7.43 (m,2H), 7.41-7.26 (m, J = 8.1 Hz, 2H), 7.25-7.12 (m, 2H), 7.10-7.02 (m, J =8.1 Hz, 2H), 5.70 (s, 2H), 4.61 (q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.0Hz, 3H). 303

533.54 534.1; 1.319 min. 304

547.57 548.0; 1.259 min. 305

576.61 577.2; 1.247 min. ¹H NMR (500 MHz, DMSO- d₆) δ 8.22 (br d, J =6.7 Hz, 1H), 8.10 (br d, J = 7.9 Hz, 1H), 8.00 (s, 1H), 7.84 (br d, J =7.9 Hz, 1H), 7.67 (br d, J = 7.6 Hz, 1H), 7.56 (br d, J = 7.9 Hz, 1H),7.34 (br d, J = 7.6 Hz, 2H), 7.28 (br s, 1H), 7.24-7.03 (m, 4H), 6.91(br d, J = 6.4 Hz, 1H), 5.70 (s, 2H), 4.60 (q, J = 7.0 Hz, 2H),3.25-3.14 (m, 6H), 1.40 (t, J = 7.0 Hz, 3H). 306

576.57 578.4; 1.192 min ¹H NMR (500 MHz, DMSO- d₆) δ 8.21 (d, J = 7.0Hz, 1H), 8.07 (br d, J = 8.2 Hz, 1H), 7.97 (s, 1H), 7.86 (d, J = 8.2 Hz,1H), 7.67 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 7.6 Hz, 1H), 7.34 (br d, J =7.9 Hz, 3H), 7.28 (br d, J = 2.4 Hz, 1H), 7.24-7.14 (m, 1H), 7.10 (br d,J = 7.9 Hz, 2H), 7.03-6.87 (m, 2H), 5.69 (s, 2H), 4.59 (q, J = 6.9 Hz,2H), 1.40 (t, J = 7.0 Hz, 3H). 307

534.53 535.2; 1.392 min. ¹H NMR (500 MHz, DMSO- d₆) δ 9.34 (s, 1H), 8.73(s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 8.19 (br d, J = 9.2 Hz, 1H), 8.08 (s,1H), 7.74 (d, J = 8.2 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.51 (d, J =7.6 Hz, 1H), 7.31 (br d, J = 7.9 Hz, 2H), 7.17 (t, J = 7.8 Hz, 1H), 7.02(br d, J = 7.9 Hz, 2H), 5.69 (s, 2H), 4.60 (q, J = 7.0 Hz, 2H), 1.42 (t,J = 7.0 Hz, 3H). 308

563.57 564.2; 1.458 min. ¹H NMR (500 MHz, DMSO- d₆) δ 8.38 (d, J = 2.5Hz, 1H), 8.08-7.94 (m, 3H), 7.67 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 7.9Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.33-7.24(m, J = 7.9 Hz, 2H), 7.16 (t, J = 7.7 Hz, 1H), 7.08-7.01 (m, J = 7.9 Hz,2H), 5.71 (s, 2H), 4.61 (q, J = 7.0 Hz, 2H), 2.57- 2.53 (m, 3H), 1.42(t, J = 7.0 Hz, 3H).

Example 309:2-ethoxy-1-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 299b (78 mg, 0.155 mmol) was dissolved in xylenes (1 mL).Tributylchlorostannane (0.126 mL, 0.466 mmol) was added followed bysodium azide (30.3 mg, 0.466 mmol). The reaction mixture was stirred at140° C. in a pressure-rated vial behind a blast shield for 18 h. Thereaction mixture was diluted with EtOAc and the azide was quenched with10% CAN (246 mg, 0.449 mmol). The reaction mixture was diluted with H₂Oand extracted with EtOAc 3×. The combined organics were washed withbrine, dried with sodium sulfate, filtered and concentrated. The cruderesidue was dissolved in 1:1 1M NaOH/MeOH (4 mL) and stirred at 65° C.for 1 h. The MeOH was evaporated off and the remaining aq. mixture wasdiluted with a small amount of H₂O and extracted (3×) with 1:1EtOAc/hexanes. The aq. mixture was then acidified to pH 3-4 with 10%citric acid and extracted with EtOAc 3×. The combined organics werewashed with brine, dried with sodium sulfate, filtered and concentrated.The crude residue was dissolved in DMF, filtered and purified by reversephase HPLC (Xbridge Prep Shield RP18, 15 min gradient of 20-100% B.A=H₂O/MeOH 10 mM NH₄OAc 90:10. B═H₂O/MeOH 10 mM NH₄OAc 10:90) to affordthe title compound (Example 309, 4.3 mg, 8.09 μmol, 10.49% yield). MS(ESI) m/z [M+H]⁺=532.2. ¹H NMR (500 MHz, DMSO-d₆) δ 8.53 (br d, J=4.3Hz, 1H), 8.18 (br d, J=7.9 Hz, 1H), 8.07 (br s, 1H), 7.95 (br s, 1H),7.74 (br d, J=7.6 Hz, 1H), 7.66 (br d, J=7.9 Hz, 1H), 7.53 (br d, J=7.6Hz, 1H), 7.35-7.14 (m, 3H), 7.10 (br d, J=7.3 Hz, 2H), 6.93 (br d, J=7.3Hz, 2H), 5.64 (br s, 2H), 4.60 (br d, J=6.7 Hz, 2H), 2.39 (br s, 3H),1.47-1.37 (m, 3H). HPLC retention time (Method A4): 1.290 min.

Example 310:2-ethoxy-1-(5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 310a: methyl1-((2′-cyano-5′-(4-methoxypyridin-2-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

Intermediate 310a was synthesized from 2-bromo-5-methoxypyridineaccording to the same procedure described for Intermediate 300c to givethe title compound

(Intermediate 310a, 21 mg, 0.040 mmol, 45.3% yield). LC-MS (Method A2):0.88 min, [M+H]⁺=519.2.

Example 310:2-ethoxy-1-(5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Example 310 was synthesized from Intermediate 310a using the proceduredescribed for Example 309 to give the title compound (Example 310, 9.6mg, 0.018 mmol, 31.4% yield). MS (ESI) m/z [M+H]⁺=548.4. ¹H NMR (500MHz, DMSO-d₆) δ 8.46 (d, J=5.7 Hz, 1H), 8.06 (br d, J=7.9 Hz, 1H), 7.98(s, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.56-7.45 (m,2H), 7.20-7.05 (m, 3H), 6.97-6.87 (m, 3H), 4.60 (q, J=7.0 Hz, 2H), 3.91(s, 3H), 1.92 (s, 3H), 1.42 (t, J=7.0 Hz, 3H. LC-MS retention time(Method A4): 1.066 min

Example 311:2-ethoxy-1-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 311a: methyl1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

To a pressure-rated vial I-005 (830 mg, 1.902 mmol),3-chloro-[1,1′-biphenyl]-4-carbonitrile (488 mg, 2.283 mmol) and secondgeneration XPHOS precatalyst (74.8 mg, 0.095 mmol) was added dioxane(9512 μl) followed by 2 M K₃PO₄ (2 M aq) (1902 μl, 3.80 mmol). Thereaction mixture was sparged with N₂ for 2 min before being sealed andheated at 85° C. for 1 h. The reaction mixture was concentrated ontocelite and purified by ISCO (0-100% EtOAc in hexane) to afford the titlecompound (Intermediate 311a, 900 mg, 1.846 mmol, 97% yield). LC-MS: MS(ESI) m/z: 488.10 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.87-7.81 (m, 1H),7.77 (d, J=8.0 Hz, 1H), 7.68-7.57 (m, 5H), 7.54-7.40 (m, 5H), 7.24-7.18(m, 1H), 7.15 (d, J=8.3 Hz, 2H), 5.73 (s, 2H), 4.71 (d, J=6.9 Hz, 2H),3.79 (s, 3H), 1.52 (t, J=7.0 Hz, 3H).

Example 311:2-ethoxy-1-(6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Example 311 was synthesized from Intermediate 311a using the proceduredescribed for Example 299 to give the title compound (Example 311, 255mg, 0.479 mmol, 61%). MS (ESI) m/z [M+H]⁺=533.4. ¹H NMR (500 MHz,DMSO-d₆) δ 7.82 (d, J=7.8 Hz, 1H), 7.77 (d, J=7.3 Hz, 2H), 7.73-7.64 (m,3H), 7.54 (d, J=7.5 Hz, 1H), 7.51-7.45 (m, 2H), 7.42 (d, J=7.2 Hz, 1H),7.33 (d, J=7.1 Hz, 2H), 7.18 (br. s., 1H), 7.06 (d, J=7.8 Hz, 2H), 5.69(br. s., 2H), 4.59 (d, J=6.9 Hz, 2H), 1.40 (t, J=6.9 Hz, 3H). LC-MSretention time (method A4): 1.830 min.

Example 312:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Example 312 was synthesized from Intermediate 311a using the sameprocedure used to synthesize Example 309 to give the title compound(Example 312, 4 mg, 7.74 μmol, 7.61% yield). MS (ESI) m/z [M+H]⁺=517.2.¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (s, 1H), 7.73 (br d, J=7.3 Hz, 2H),7.66 (s, 2H), 7.59-7.49 (m, 2H), 7.49-7.42 (m, 3H), 7.40-7.26 (m, J=7.0Hz, 1H), 7.17-7.06 (m, 3H), 6.91 (br d, J=7.9 Hz, 2H), 5.66 (s, 2H),4.58 (br d, J=7.0 Hz, 2H), 1.41 (br t, J=7.0 Hz, 3H). LC-MS retentiontime (Method A4): 1.7969 min

Example 313:1-((6′-carboxy-3″-methyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 313a: methyl1-((5′-chloro-2′-(methoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

To a vial was added I-005 (221 mg, 0.506 mmol), methyl4-chloro-2-iodobenzoate (150 mg, 0.506 mmol) and PdCl₂(dppf)CH₂Cl₂(20.66 mg, 0.025 mmol). THF (3 mL) and 1.5 M Na₂CO₃ (1.012 mL, 1.518mmol) were added. The mixture was bubbled with Ar for 3 min. Thereaction mixture was sealed and irradiated in a microwave reactor at100° C. for 30 min. The reaction mixture was diluted with EtOAc and H₂Oand extracted with EtOAc. The combined organic layer was washed withbrine, dried with MgSO₄ and concentrated. The crude residue was purifiedby ISCO (0-100% EtOAc in Hexanes) to afford the title compound (Example313a, 160 mg, 0.334 mmol, 66.0% yield). MS (ESI) (m/z) 479 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 7.79-7.72 (m, 2H), 7.56 (dd, J=8.0, 0.8 Hz, 1H),7.38 (dd, J=8.3, 2.2 Hz, 1H), 7.32-7.25 (m, 1H), 7.23-7.18 (m, 1H), 7.17(d, J=8.3 Hz, 2H), 7.02 (d, J=8.3 Hz, 2H), 5.68 (s, 2H), 4.15 (q, J=7.2Hz, 2H), 3.79 (s, 3H), 3.57 (s, 3H), 1.52 (t, J=7.0 Hz, 3H).

Example 313:1-((6′-carboxy-3″-methyl-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

A solution of Intermediate 313a (25 mg, 0.052 mmol), m-tolylboronic acid(21.29 mg, 0.157 mmol) and Pd-XPhos G3 (2.209 mg, 2.61 μmol) in THF (1mL) and phosphoric acid, potassium salt (1.0 M aq.) (0.094 mL, 0.094mmol) was degased with Ar for 1 min. The reaction mixture was sealed andheated at 140° C. in a microwave reactor for 30 min 0.5 ml of MeOH wasthen added to the mixture followed by NaOH (0.157 mL, 0.313 mmol). Themixture was heated up in microwave for 15 min at 100° C. Additional NaOH(0.157 mL, 0.313 mmol) was added to the mixture and the mixture wasstirred at 100° C. for 30 min. The mixture was filtrated and purified byvia preparative LC-MS with the following conditions: Column: XBridgeC18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mMNH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient:10-50% B over 22 minutes, then a 4-minute hold at 100% B; Flow: 20mL/min to afford the title compound (Example 313, 13.3 mg, 0.025 mol,48%). MS (ESI) m/z [M+H]⁺=507.4. ¹H NMR (500 MHz, DMSO-d₆) δ 7.74-7.61(m, 2H), 7.54 (s, 1H), 7.52-7.45 (m, 3H), 7.40 (br d, J=7.3 Hz, 1H),7.36-7.29 (m, 3H), 7.19 (br d, J=7.6 Hz, 1H), 7.15-7.04 (m, 3H), 5.76(s, 2H), 4.58 (q, J=7.0 Hz, 2H), 2.36 (s, 3H), 1.42 (t, J=7.0 Hz, 3H).LC-MS retention time (Method A4): 1.986 min

Example 314:1-((6′-carboxy-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 314a: methyl2-ethoxy-1-((6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate

To a solution of methyl 2-ethoxy-1H-benzo[d]imidazole-7-carboxylate(55.5 mg, 0.252 mmol) in DMF (2 mL) was added sodium hydride (60%)(16.78 mg, 0.420 mmol) at RT. The reaction mixture was stirred for 10min at RT before methyl4″-(bromomethyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylate (Intermediate400b, 80 mg, 0.210 mmol) was added in its own solution of DMF (1 mL).After 50 min of stirring at RT the reaction mixture was diluted withEtOAc and washed with 10% LiCl (aq). The organic phase was dried overMgSO₄, filtered over celite, and concentrated. The residue was dissolvedDMF and purified by ISCO (0-100% EtOAc/Hexanes) to afford the titlecompound (Intermediate 314a, 48 mg, 0.069 mmol, 33.0% yield). LC-MSRetention time (Method A2)=1.20 min. Found m/z: 520.1 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.89 (d, J=8.1 Hz, 1H), 7.66-7.57 (m, 4H), 7.55-7.49(m, 2H), 7.49-7.31 (m, 4H), 7.22 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.1 Hz,2H), 5.66 (s, 2H), 4.68 (q, J=7.1 Hz, 2H), 3.78 (s, 3H), 3.57 (s, 3H),1.54-1.48 (m, 3H).

Example 314:1-((6′-carboxy-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 314a (36 mg, 0.069 mmol) was suspended in a solution ofNaOH (1 M NaOH) (2.075 mL, 2.075 mmol) and THF (2 mL) and heated at 65°C. for 3 h. The reaction mixture was diluted with EtOAc and washed with1 M HCl. The aqueous phase was back extracted a second time with EtOAcand the organic phases were concentrated. The crude residue was retakenin DMF, filtered and purified by reverse phase HPLC Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂O with 0.1%trifluoroacetic acid; Gradient: 30-70% B over 20 minutes, then a3-minute hold at 100% B; Flow: 20 mL/min) to afford the title compound(Example 314, 16 mg, 0.032 mmol, 46%). MS (ESI) m/z [M+H]⁺=493.1. ¹H NMR(500 MHz, DMSO-d₆) δ 7.79 (d, J=7.9 Hz, 1H), 7.75-7.68 (m, 3H), 7.65 (d,J=7.6 Hz, 1H), 7.56-7.51 (m, 2H), 7.49-7.43 (m, 2H), 7.42-7.36 (m, 1H),7.32 (d, J=7.9 Hz, 2H), 7.18 (t, J=7.8 Hz, 1H), 7.05 (d, J=7.9 Hz, 2H),5.69 (s, 2H), 4.61 (q, J=7.0 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H). LC-MSretention time (Method A4): 1.846 min

Example 315:2-ethoxy-1-(6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate

To a vial containing Intermediate 313a (18 mg, 0.038 mmol) was added 2ndgeneration ruphos precatalyst (5.84 mg, 7.52 μmol) followed sodiumtert-butoxide (21.67 mg, 0.226 mmol). THF (1 mL) was then added followedby 3,3-difluoropiperidine, HCl (30 mg, 0.188 mmol). The reaction wasdegassed with Na. The reaction vial was sealed and heated at 65° C. for18 h. The reaction mixture was then diluted with EtOAc and filteredthrough celite. The filtrate was concentrated. The crude residue wasdissolved in MeOH (1 mL). 1M NaOH (0.752 mL, 0.752 mmol) was added andthe reaction was allowed to stir at 65° C. for 1 h. The reaction mixturewas then acidified to pH 3-4 with 5% citric acid and extracted (3×) withEtOAc. The combined organics were washed with brine, dried with sodiumsulfate, filtered and concentrated. The crude residue was dissolved inDMF, filtered and purified by reverse phase HPLC (Xbridge Prep ShieldRP18, 15 min gradient of 20-100% B. A=H₂O/MeOH 10 mM NH₄OAc 90:10.B═H₂O/MeOH 10 mM NH₄OAc 10:90) to afford the title compound (Example315, 2.6 mg, 4.85 μmol, 12.92% yield). MS (ESI) m/z [M+H]⁺=536.0. ¹H NMR(500 MHz, DMSO-d₆) δ 7.65 (br s, 2H), 7.46 (br s, 1H), 7.42 (br s, 1H),7.27-7.07 (m, 3H), 7.04 (br s, 2H), 6.97 (br s, 2H), 6.68 (br s, 1H),5.75 (br s, 2H), 4.57 (br d, J=6.4 Hz, 2H), 2.05 (br d, J=16.8 Hz, 2H),1.91 (br s, 2H), 1.73 (br s, 2H), 1.41 (br t, J=6.7 Hz, 3H), 1.00 (br d,J=6.4 Hz, 1H. LC-MS retention time (Method A4): 1.661 min

Example 316: methyl2-ethoxy-1-(6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate

Example 316 was synthesized from Intermediate 311a using the sameprocedure described for Example 299, however, the reaction sequence wasstopped prior to the ester hydrolysis. The crude residue was purified byreverse phase HPLC (Xbridge Prep Shield RP18, 15 min gradient of 20-100%B. A=H₂O/MeOH 10 mM NH₄OAc 90:10. B═H₂O/MeOH 10 mM NH₄OAc 10:90) toafford the title compound (Example 316, 2.9 mg, 5.31 μmol, 19.33%yield). MS (ESI) m/z [M+H]⁺=547.1. ¹H NMR (500 MHz, DMSO-d₆) δ 7.95-7.25(m, 11H), 7.20 (t, J=7.9 Hz, 2H), 6.93 (br. s., 2H), 5.49 (br. s., 2H),4.59 (q, J=6.8 Hz, 2H), 3.73 (br. s., 3H), 1.39 (t, J=6.9 Hz, 3H). LC-MSretention time (Method A4): 2.198 min

Example 317:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-hydroxy-1H-benzo[d]imidazole-7-carboxylicacid

To a small vial containing Intermediate 311a (30 mg, 0.062 mmol) wasadded dibutyltin oxide (15.32 mg, 0.062 mmol) and toluene (1 mL)followed by TMS-N₃ (0.041 mL, 0.308 mmol). The reaction mixture wassealed and heated at 100° C. behind a blast shield overnight. Thereaction mixture was concentrated and the crude residue was dissolved inMeOH (2 mL). NaOH (170 mg, 4.24 mmol) was added followed by Water (2mL). The reaction mixture was stirred at 75° C. for 45 minutes. Thereaction mixture was diluted with MeOH and neutralized with AcOH. Thereaction mixture was concentrated, azeotroped with toluene 2× thenre-dissolved in DMF filtered and purified by reverse phase HPLC (XbridgePrep Shield RP18, 15 min gradient of 20-100% B. A=H₂O/MeOH 10 mM NH₄OAc90:10. B═H₂O/MeOH 10 mM NH₄OAc 10:90) to afford the title compound(Example 317, 1.6 mg, 3.24 mol, 5.73% yield). MS (ESI) m/z [M+H]⁺=489.1.¹H NMR (500 MHz, DMSO-d₆) δ 7.74 (d, J=7.5 Hz, 2H), 7.68 (br. s., 2H),7.56 (s, 1H), 7.50-7.42 (m, 2H), 7.41-7.32 (m, 1H), 7.27 (d, J=6.8 Hz,1H), 7.19-6.86 (m, 6H), 5.40 (br. s., 2H). LC-MS retention time (MethodA4): 1.126 min.

Example 318:1-((2′-carboxy-5′-(2-methoxypyridin-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

To a pressure-rated vial containing Intermediate 313a (18 mg, 0.038mmol), (2-methoxypyridin-3-yl)boronic acid (17.24 mg, 0.113 mmol) andsecond generation XPHOS precatalyst (8.87 mg, 0.011 mmol) was addeddioxane (500 μl) followed by 2 M K₃PO₄ (2 M aq) (94 μl, 0.188 mmol). Thereaction mixture was sparged with N₂ for 2 min before being sealed andheated at 65° C. The reaction mixture was diluted with EtOAc andfiltered through celite. The filtrate was concentrated and the cruderesidue was dissolved in MeOH (1 mL). 1M NaOH (752 μl, 0.752 mmol) wasadded and the reaction was allowed to stir at 65° C. for 1 hour. Thereaction mixture was then acidified to pH 3-4 with 5% citric acid andextracted (3×) with EtOAC. The combined organics were washed with brine,dried with sodium sulfate, filtered and concentrated. The crude residuewas dissolved in DMF, filtered and purified by reverse phase HPLC(Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95ACN: H₂O with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂Owith 0.1% trifluoroacetic acid; Gradient: 20-60% B over 20 minutes, thena 4-minute hold at 100% B; Flow: 20 mL/min) to afford the title compound(Example 318, 5.5 mg, 10.51 mol, 28.0% yield). MS (ESI) m/z[M+H]⁺=524.2. ¹H NMR (500 MHz, DMSO-d₆) δ 8.20 (br d, J=3.7 Hz, 1H),7.83 (br d, J=6.4 Hz, 1H), 7.75 (br d, J=7.9 Hz, 1H), 7.70-7.58 (m, 2H),7.54 (br d, J=7.0 Hz, 1H), 7.45 (br s, 1H), 7.30 (br d, J=7.0 Hz, 2H),7.18 (br s, 1H), 7.12-7.07 (m, 1H), 7.04 (br d, J=7.3 Hz, 2H), 5.69 (brs, 2H), 4.61 (q, J=7.0 Hz, 2H), 3.87 (s, 3H), 1.42 (br t, J=6.9 Hz, 3H.LC-MS retention time (Method A4): 1.661 min

Example 319:1-((2′-carboxy-5′-(3,3-dimethylindolin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Example 319 was synthesized from 3,3-dimethylindoline and Intermediate313a according to the same procedure described for the synthesis ofExample 315 to give the title compound (Example 319, 0.6 mg, 1.068 μmol,2.84% yield). MS (ESI) m/z [M+H]⁺=562.1. ¹H NMR (500 MHz, DMSO-d₆) δ7.76 (br s, 1H), 7.48-7.28 (m, 3H), 7.27-7.08 (m, 7H), 7.03 (br d, J=5.4Hz, 1H), 6.90 (br s, 1H), 6.82 (br t, J=6.8 Hz, 1H), 5.82 (br s, 2H),4.55 (br d, J=6.7 Hz, 2H), 3.73 (br s, 2H), 3.52-3.33 (m, 2H), 3.17 (s,1H), 1.40 (br t, J=6.6 Hz, 3H), 1.28 (br s, 6H), 1.00 (br d, J=6.3 Hz,1H. LC-MS retention time (Method A4): 2.137 min

Example 320:1-((6′-carboxy-4″-(dimethylcarbamoyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Example 320 was synthesized from Intermediate 313a and(4-(dimethylcarbamoyl)phenyl)boronic acid using the procedure that wasdescribed for Example 299b to give the title compound (Example 320, 5.9mg, 10.47 μmol, 27.9% yield). MS (ESI) [M+H]⁺=564.0. LC-MS retentiontime (Method A4): 1.533 min

Example 321:1-((4″-(dimethylcarbamoyl)-6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 321a: methyl1-((6′-cyano-4″-(dimethylcarbamoyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

Intermediate 321a was synthesized from Intermediate 300a and(4-(dimethylcarbamoyl)phenyl)boronic acid using the procedure that wasused to synthesize Intermediate 299b to afford the title compound(Intermediate 321a, 40 mg, 0.072 mmol, 45.6% yield). MS (ESI) m/z[M+H]⁺=559.7. LC-MS retention time (Method A2): 0.97 min

Example 321:1-((4″-(dimethylcarbamoyl)-6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Example 321 was synthesized from Intermediate 321a using the proceduredescribed for Example 299 to give the title compound (Example 321, 4.9mg, 8.12 μmol, 11.34% yield). MS (ESI) m/z [M+H]⁺=604.5. ¹H NMR (500MHz, DMSO-d₆) δ 7.81 (br d, J=8.2 Hz, 3H), 7.75-7.57 (m, 3H), 7.56-7.42(m, 3H), 7.30 (br d, J=7.9 Hz, 2H), 7.17 (s, 1H), 7.05 (br d, J=8.2 Hz,2H), 5.66 (s, 2H), 4.57 (br d, J=7.0 Hz, 2H), 2.99 (br s, 3H), 2.93 (brs, 3H), 1.38 (t, J=7.0 Hz, 3H. LC-MS retention time (Method A4): 1.479min

Example 322:1-((5′-(1H-indol-3-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Example 322 was synthesized from Intermediate 313a and3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole using thesequence described for Example 321 to give the title compound (Example322, 130 mg, 0.247 mmol, 73.2% yield). MS (ESI) m/z [M+H]⁺=572.2. ¹H NMR(500 MHz, DMSO-d₆) δ 11.57 (br s, 1H), 8.00-7.79 (m, 3H), 7.75-7.61 (m,3H), 7.55 (br d, J=7.6 Hz, 1H), 7.47 (br d, J=8.0 Hz, 1H), 7.34 (br d,J=8.1 Hz, 2H), 7.25-7.11 (m, 3H), 7.08 (br d, J=8.0 Hz, 2H), 5.70 (s,2H), 4.66-4.56 (m, 2H), 3.18 (s, 1H), 2.08 (s, 1H), 1.41 (t, J=7.0 Hz,3H). LC-MS retention time (Method A4): 1.722 min

Example 323: methyl(R)-1-((2′-cyano-5′-(3-methylpiperidin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

Intermediate 323a: methyl1-((2′-cyano-5′-fluoro-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

To a solution of I-005 (600 mg, 1.375 mmol) and2-bromo-4-fluorobenzonitrile (330 mg, 1.650 mmol) in 4:1 toluene/EtOH(12 mL) was added K₃PO₄ (2 M, aq) (2.063 mL, 4.13 mmol) followed byPdCl₂(dppf) (101 mg, 0.138 mmol). The resulting mixture was sparged withN₂ for 2 min before being sealed and heated at 120° C. for 45 min in themicrowave. Additional PdCl₂(dppf) (101 mg, 0.138 mmol) was added to thereaction mixture which was then evacuated and backfilled with N₂ (3×)and stirred for an additional 45 min in the microwave at 120° C. Thereaction mixture was then concentrated onto celite and purified by ISCO(80 g column 0-100% EtOAc/Hexanes) to afford the title compound(Intermediate 323a, 400 mg, 0.931 mmol, 67.7% yield). LC-MS: MS (ESI)m/z: 430.1 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.77 (d, J=7.9 Hz, 2H),7.59 (d, J=7.7 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.23-7.09 (m, 5H), 5.73(s, 2H), 4.73-4.67 (m, 2H), 3.78 (s, 3H), 1.51 (t, J=7.2 Hz, 3H).

Intermediate 323b: methyl(R)-1-((2′-cyano-5′-(3-methylpiperidin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

Intermediate 323a (190 mg, 0.442 mmol) was dissolved in DMSO (1475 μl).Potassium carbonate (306 mg, 2.212 mmol) was added followed by(R)-3-methylpiperidine, HCl (132 mg, 0.973 mmol). The reaction wassealed and heated at 100° C. behind a blast shield for a total of 2hours. The reaction mixture diluted with EtOAc and H₂O. The aqueousphase was extracted (3×) with EtOAc and the combined organic phases werewashed with brine, dried with sodium sulfate, filtered and concentrated.The crude residue was purified by ISCO (0-100% EtOAc in hexane) toafford the title compound (Intermediate 323b, 140 mg, 0.275 mmol, 62.2%yield). LC-MS (Method A2): 1.11 min, [M+H]⁺=509.0.

Example 323: methyl(R)-1-((2′-cyano-5′-(3-methylpiperidin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

Example 323 was synthesized from Intermediate 323b using the sameprocedure as described for Example 309 to give the title compound(Example 323, 3.6 mg, 6.70 μmol, 7.74% yield). MS (ESI) [M+H]⁺=538.2. ¹HNMR (500 MHz, DMSO-d₆) δ 7.63 (d, J=7.9 Hz, 1H), 7.50 (d, J=7.6 Hz, 1H),7.41 (d, J=8.5 Hz, 1H), 7.16 (br t, J=7.6 Hz, 1H), 7.07-6.95 (m, 3H),6.90 (br d, J=7.9 Hz, 2H), 6.85-6.66 (m, 1H), 5.62 (s, 2H), 4.59 (q,J=7.0 Hz, 2H), 3.73 (br s, 2H), 2.68 (br s, 1H), 2.48-2.36 (m, 1H),1.80-1.53 (m, 5H), 1.41 (t, J=7.0 Hz, 3H), 0.90 (d, J=6.7 Hz, 3H). LC-MSretention time (Method A4): 1.559 min.

Example 324:(S)-2-ethoxy-1-(5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Example 324 was synthesized from I-005 and (S)-3-methylpiperidine, HClaccording to the same sequence described for Example 323. MS (ESI) m/z[M+H]⁺=538.0. ¹H NMR (500 MHz, DMSO-d₆) δ 7.61 (d, J=7.8 Hz, 1H), 7.52(br d, J=7.7 Hz, 1H), 7.42 (d, J=8.6 Hz, 1H), 7.16 (t, J=7.8 Hz, 2H),7.07-6.98 (m, 3H), 6.93 (br d, J=8.1 Hz, 2H), 6.87-6.76 (m, 1H), 5.64(s, 2H), 4.59 (q, J=7.0 Hz, 2H), 3.80-3.66 (m, 2H), 2.73 (br s, 1H),2.48-2.34 (m, 1H), 1.76 (br d, J=12.7 Hz, 1H), 1.74-1.63 (m, 2H), 1.55(br d, J=12.0 Hz, 1H), 1.40 (t, J=7.1 Hz, 3H), 1.17-1.01 (m, 1H), 0.91(d, J=6.6 Hz, 3H). LC-MS retention time (Method A4): 1.561 min

Example 325:(R)-2-ethoxy-1-(5′-(3-methylpiperidin-1-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Example 325 was synthesized from Intermediate 323b according to the sameprocedure used to synthesize Example 299 to give the title compound(Example 325, 3.4 mg, 6.14 μmol, 2.403% yield). LC-MS (Method A4):1.745min, [M+H]⁺=554.3;

Example 326:2-ethoxy-1-(5′-(quinolin-3-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 326a: methyl1-((2′-cyano-5′-(quinolin-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

To a pressure-rated vial containing Intermediate 300a (75 mg, 0.168 mmol) and second generation XPHOS precatalyst (33.1 mg, 0.042 mmol) wasadded dioxane (2000 μl) followed by 2 M K₃PO₄ (2 M aq) (168 μl, 0.336mmol). The reaction mixture was evacuated and backfilled with N₂ (3×)before being sealed and heated at 85° C. for 1 h. The reaction mixturewas diluted with EtOAc, filtered and concentrated onto celite andpurified by ISCO (0-100% EtOAc in hexanes) to afford the title compound(Intermediate 326a, 50 mg, 0.093 mmol, 55.2% yield). LC-MS (Method A2):0.91 min, [M+H]⁺=539.0.

Example 326:2-ethoxy-1-(5′-(quinolin-3-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Example 326 was synthesized from Intermediate 326a according to the sameprocedure used to synthesize Example 309 to give the title compound(Example 326, 18 mg, 0.032 mmol, 34.2% yield). MS (ESI) m/z[M+H]⁺=568.0. ¹H NMR (500 MHz, DMSO-d₆) δ 9.38 (d, J=1.8 Hz, 1H),8.91-8.77 (m, 1H), 8.13-8.04 (m, 3H), 7.98 (s, 1H), 7.87-7.78 (m, 2H),7.72-7.63 (m, 2H), 7.56 (d, J=7.6 Hz, 1H), 7.25-7.11 (m, 3H), 6.99 (brd, J=7.9 Hz, 2H), 5.67 (s, 2H), 4.60 (q, J=7.0 Hz, 2H), 3.01 (s, 1H),1.41 (t, J=7.2 Hz, 3H). LC-MS retention time (Method A4): 1.324 min

Example 327:1-((5′-(1-(difluoromethyl)-1H-pyrazol-4-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Example 327 was synthesized from Intermediate 300a and1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleaccording to the same sequence described for Example 326 to give thetitle compound (Example 327, 20 mg, 0.036 mmol, 35.1% yield). MS (ESI)[M+H]⁺=557.3. ¹H NMR (500 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.33 (s, 1H),7.96 (s, 1H), 7.79 (s, 1H), 7.71-7.65 (m, 1H), 7.63-7.57 (m, 2H), 7.52(br d, J=7.6 Hz, 1H), 7.42 (br d, J=7.6 Hz, 1H), 7.13-7.02 (m, 3H), 6.92(br d, J=7.6 Hz, 2H), 5.68 (s, 2H), 4.58 (q, J=6.7 Hz, 2H), 1.42 (t,J=7.0 Hz, 3H). LC-MS retention time (Method A4): 1.490 min.

Example 328:2-ethoxy-1-(5′-(6-methoxy-5-methylpyridin-3-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Example 328 was synthesized from Intermediate 300a and(6-methoxy-5-methylpyridin-3-yl)boronic acid according to the samesequence described for Example 326 to give the title compound (Example328, 0.8 mg, 0.0014 mmol, 1.6% yield). MS (ESI) [M+H]⁺=562.2. ¹H NMR(500 MHz, DMSO-d₆) δ 8.51-8.37 (m, 1H), 8.03 (s, 1H), 7.84 (d, J=7.9 Hz,1H), 7.75-7.65 (m, 3H), 7.55 (d, J=7.6 Hz, 1H), 7.19 (s, 1H), 7.11 (brd, J=8.2 Hz, 2H), 6.96 (br d, J=7.9 Hz, 2H), 5.65 (s, 2H), 4.59 (d,J=7.0 Hz, 2H), 3.93 (s, 3H), 2.21 (s, 3H), 1.40 (t, J=7.0 Hz, 3H). LC-MSretention time (Method A4): 1.814 min

Example 329:2-ethoxy-1-(5′-(2-methoxypyridin-3-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Example 329 was synthesized from Intermediate 300a and2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine usingthe sequence described for Example 321 to give the title compound(Example 329, 6.9 mg, 0.012 mmol, 17.3%). MS (ESI) m/z [M+H]⁺=564.2. ¹HNMR (500 MHz, DMSO-d₆) δ 8.19 (br d, J=4.6 Hz, 1H), 7.83 (br d, J=7.3Hz, 1H), 7.73-7.57 (m, 3H), 7.53 (s, 2H), 7.26 (br d, J=7.6 Hz, 2H),7.17 (br s, 1H), 7.12-7.07 (m, 1H), 7.04 (br d, J=7.9 Hz, 2H), 5.66 (brs, 2H), 4.62-4.50 (m, 2H), 3.86 (s, 2H), 2.57-2.54 (m, 2H), 1.37 (t,J=7.0 Hz, 3H). LC-MS retention time (Method A4): 1.730 min

Example 330:2-Ethoxy-1-((5′-phenoxy-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 330a: Methyl1-(4-bromobenzyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

To a 50 mL pressure vessel containing methyl2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (1.00 g, 4.54 mmol) wasadded 2-propanol (15 mL) and potassium carbonate (1.25 g, 9.08 mmol) andthe mixture was stirred at 30° C. for 5 min. To this mixture was added1-bromo-4-(bromomethyl)benzene (1.19 g, 4.77 mmol) andtetrabutylammonium iodide (0.084 g, 0.23 mmol) and the temperature ofthe reaction was raised to 45° C. After 60 min an additional 15 mL of2-propanol was added and the reaction was stirred at the sametemperature for another 90 min. The cooled reaction mixture was dilutedwith EtOAc (200 mL) and H₂O (50 mL), the layers were separated and theorganic phase was washed (brine), dried (anhydrous sodium sulfate),filtered and evaporated. The residue was dry-packed onto silica gel (15g) and purified on a 40 gram column (ISCO/0-60% EtOAc-hexane) to providethe title compound as a pale yellow solid (1.50 g, 3.86 mmol, 85%yield). LC-MS (Method H): 1.38 min, [M+H]⁺=389.0; ¹H NMR (400 MHz,CDCl₃) δ ppm 7.73 (dd, J=7.8, 1.2 Hz, 1H), 7.58 (dd, J=7.8, 1.2 Hz, 1H),7.33-7.39 (m, 2H), 7.18 (t, J=8.0 Hz, 1H), 6.87 (m, J=8.6 Hz, 2H), 5.58(s, 2H), 4.65 (q, J=7.2 Hz, 2H), 3.76 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).

Intermediate 330b: Methyl1-02′-cyano-5′-fluoro-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

In a 20 mL pressure vessel containing Intermediate 330a (0.750 g, 1.93mmol) and4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(0.952 g, 3.85 mmol) was added ethanol/toluene (10 mL, 1:9) and 2Maqueous Na₂CO₃ (2.89 mL, 5.78 mmol). The mixture was purged with astream of Ar for 10 min and thentetrakis(triphenylphosphine)palladium(0) (0.223 g, 0.193 mmol) wasadded, the vial was sealed and the mixture was stirred at 110° C. for 3h.

The cooled mixture was diluted with EtOAc (50 mL) and then it was washed(H₂O, brine), dried with anhydrous sodium sulfate, filtered andevaporated. The residue was dry-packed onto silica gel and purified byflash chromatography on a 25 gram column (ISCO/0 to 30% EtOAc/hexane) toprovide the title compound as an off-white solid (0.800 g, 1.86 mmol,97% yield). LC-MS (Method H): 1.36 min, [M+H]⁺=430.1; 4 ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.03 (dd, J=8.6, 5.9 Hz, 1H), 7.71 (dd, J=7.8, 1.2 Hz,1H), 7.53 (m, J=8.2 Hz, 2H), 7.40-7.51 (m, 3H), 7.20 (t, J=7.8 Hz, 1H),7.09 (m, J=8.2 Hz, 2H), 5.58 (s, 2H), 4.62 (q, J=7.0 Hz, 2H), 3.70 (s,3H), 1.40 (t, J=7.0 Hz, 3H).

Intermediate 330c: Methyl1-((2′-cyano-5′-phenoxy-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

To a solution of Intermediate 330b (0.050 g, 0.116 mmol) in DMF (2 mL)was added phenol (0.022 g, 0.233 mmol) and cesium carbonate (0.114 g,0.349 mmol) and the mixture was stirred at 100° C. for 18 h. Aftercooling to RT, dimethyl sulfoxide (3.5 mL) and formic acid (0.044 mL,1.16 mmol) were added and the mixture was filtered. The title compoundwas isolated by reverse phase HPLC (Method F, using formic acid asmodifier) to afford a white solid (0.043 g, 0.085 mmol, 73% yield).LC-MS (Method H): 1.47 min, [M+H]⁺=504.1; HRMS (ESI): Calcd. forC₃₁H₂₆N₃O₄ [M+H]⁺ m/z 504.1918; found: 504.1909.

Example 330:2-Ethoxy-1-((5′-phenoxy-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

To a mixture of Intermediate 330c (0.033 g, 0.066 mmol) in o-xylene (3mL) was added azidotributylstannane (0.054 mL, 0.197 mmol), the reactionvessel was sealed and the mixture was heated at 140° C. for 6 days. Thevolatiles were then removed under reduced pressure and ethanol (3 mL)was added, followed by 2 M aqueous LiOH (0.492 mL, 0.963 mmol). Theresulting mixture was stirred at RT for 20 h and then the volatiles wereevaporated and EtOAc (3 mL) was added to give a biphasic mixture whichwas centrifuged at approximately 1000 g. The supernatant was removed andthe white residue was dissolved in H₂O (3 mL) and AcOH (0.075 mL, 1.31mmol) was added. The resulting suspension was centrifuged atapproximately 1000 g and then the supernatant was removed and the solidresidue was taken up in DMSO (3 mL) and the solution was submitted toreverse phase HPLC purification (Method F, using formic acid asmodifier) to afford the title compound as a white solid (0.025 g, 0.047mmol, 71% yield). LC-MS (Method H): 1.44 min, [M+H]⁺=533.1; HRMS (ESI):Calcd. for C₃₀H₂₅N₆O₄ [M+H]⁺ m/z 533.1932; found: 533.1931; ¹H NMR (400MHz, DMSO-d₆) δ ppm 13.25 (br s, 2H), 7.64 (dd, J=7.6, 6.1 Hz, 2H), 7.52(d, J=7.8 Hz, 1H), 7.38-7.48 (m, 2H), 7.06-7.26 (m, 5H), 7.03 (br s,1H), 6.99 (m, J=7.8 Hz, 2H), 6.91 (m, J=8.2 Hz, 2H), 5.61 (s, 2H), 4.56(q, J=7.0 Hz, 2H), 1.36 (t, J=7.0 Hz, 3H).

The following examples have been similarly prepared from Intermediate330b and the appropriate phenols, hydroxypyridines or azoles, using amethod as described for the synthesis of Example 330 above. AnalyticalLC-MS injections were used to determine the final purity and theretention time is reported for each compound, as determined by MethodA1, Method A2 or Method H.

LC-MS m/z [M + H]⁺; ¹H NMR (400 MHz, Ex Structure MW RT (Method)DMSO-d₆) δ ppm 331

550.54 551.1; 1.53 min (Method H) 13.13 (br s, 2H), 7.65 (dd, J = 7.8,5.5 Hz, 2 H), 7.52 (d, J = 7.8 Hz, 1 H), 7.42- 7.50 (m, 1 H), 7.13-7.20(m, 2 H), 7.09-7.13 (m, 1H), 6.94-7.09 (m, 5 H), 6.91 (d, J = 8.2 Hz, 2H), 5.61 (s, 2 H), 4.56 (q, J = 7.0 Hz, 2 H), 1.36 (t, J = 7.0 Hz, 3 H).332

562.58 563.1; 1.37 min (Method H) 13.10 (br s, 2 H), 7.59-7.68 (m, 2 H),7.52 (d, J = 6.7 Hz, 1 H), 7.33 (t, J = 8.2 Hz, 1 H), 7.16 (t, J = 7.8Hz, 1 H), 7.11 (dd, J = 8.4, 2.5 Hz, 1 H), 7.04 (d, J = 2.3 Hz, 1 H),6.99 (m, J = 8.2 Hz, 2 H), 6.91 (m, J = 8.2 Hz, 2 H), 6.79 (dd, J = 8.2,2.0 Hz, 1 H), 6.72 (t, J = 2.2 Hz, 1 H), 6.69 (dd, J = 8.2, 2.0 Hz, 1H), 5.61 (s, 2 H), 4.56 (q, J = 7.0 Hz, 2 H), 3.75 (s, 3 H), 1.36 (t, J= 7.0 Hz, 3 H). 333

533.54 534.1; 1.26 min (Method H) 13.16 (br s, 2 H), 8.49 (br s, 1 H),8.43 (d, J = 3.5 Hz, 1 H), 7.56-7.71 (m, 3 H), 7.42-7.56 (m, 2 H), 7.05-7.23 (m, 3 H), 6.85-7.05 (m, 4 H), 5.61 (br s, 2 H), 4.56 (q, J = 7.0Hz, 2 H), 1.36 (t, J = 6.8 Hz, 3 H). 334

550.54 551.1; 1.34 min (Method H) 13.12 (s, 2 H), 7.59-7.68 (m, 2 H),7.52 (d, J = 7.8 Hz, 1 H), 7.38-7.47 (m, 1 H), 7.22-7.38 (m, 3 H), 7.16(t, J = 7.8 Hz, 1 H), 7.01-7.09 (m, 2 H), 6.99 (m, J = 7.8 Hz, 2 H),6.91 (m, J = 8.2 Hz, 2 H), 5.61 (s, 2 H), 4.56 (q, J = 7.0 Hz, 2 H),1.36 (t, J = 7.0 Hz, 3 H). 335

616.55 617.1, 1.42 min (Method H) 13.12 (br s, 2 H), 7.60-7.72 (m, 2 H),7.48-7.59 (m, 2 H), 7.09-7.24 (m, 6 H), 7.00 (m, J = 8.2 Hz, 2 H), 6.91(m, J = 8.2 Hz, 2 H), 5.61 (s, 2 H), 4.56 (q, J = 7.0 Hz, 2 H), 1.36 (t,J = 7.0 Hz, 3 H). 336

550.54 551.1; 1.36 min (Method H) 13.14 (br s, 2 H), 7.64 (t, J = 8.8Hz, 2 H), 7.52 (d, J = 7.4 Hz, 1 H), 7.12-7.32 (m, 5 H), 7.08 (dd, J =8.6, 2.7 Hz, 1 H), 6.94-7.04 (m, 3 H), 6.84-6.94 (m, 2 H), 5.61 (s, 2H), 4.56 (q, J = 6.8 Hz, 2 H), 1.36 (t, J = 7.0 Hz, 3 H). 337

547.56 548.1; 1.27 min (Method H) 13.14 (br s, 2 H), 8.28-8.41 (m, 2 H),7.62 (d, J = 8.6 Hz, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 7.8Hz, 1 H), 7.42 (d, J = 4.7 Hz, 1 H), 7.16 (t, J = 7.8 Hz, 1 H),6.95-7.04 (m, 4 H), 6.85-6.95 (m, 2 H), 5.61 (s, 2 H), 4.56 (q, J = 7.0Hz, 2 H), 2.21 (s, 3 H), 1.36 (t, J = 7.0 Hz, 3H). 338

574.51 575.1; 1.34 min (Method H) 13.11 (br s, 2 H) 8.93 (br s, 1 H),8.08 (dd, J = 8.4, 2.2 Hz, 1 H), 7.94-8.01 (m, 1 H), 7.84 (d, J = 8.2Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.54 (d, J = 7.4 Hz, 1 H), 7.17 (t,J = 7.8 Hz, 1 H), 7.05-7.14 (m, 3 H), 6.97 (d, J = 7.8 Hz, 2 H), 5.65(s, 2 H), 4.58 (q, J = 7.0 Hz, 2 H), 1.39 (t, J = 7.0 Hz, 3 H). 339

556.57 557.2; 1.29 min (Method H) 13.15 (br s, 2 H), 8.72 (s, 1 H),7.84-7.94 (m, 2 H), 7.71-7.83 (m, 3 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.54(d, J = 7.8 Hz, 1 H), 7.28-7.40 (m, 2 H), 7.08-7.21 (m, 3 H), 6.97 (d, J= 7.8 Hz, 2 H), 5.65 (s, 2 H), 4.58 (q, J = 7.0 Hz, 2 H), 1.38 (t, J =7.0 Hz, 3 H). 340

520.54 521.2; 1.26 min (Method H) 13.16 (br s, 2 H), 8.47 (s, 1 H), 7.97(dd, J = 8.4, 2.2 Hz, 1 H), 7.86 (d, J = 2.0 Hz, 1 H), 7.74 (d, J = 8.6Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.62 (s, 1 H), 7.54 (d, J = 7.8 Hz,1 H), 7.18 (t, J = 7.8 Hz, 1 H), 7.08 (m, J = 8.2 Hz, 2 H), 6.95 (m, J =8.2 Hz, 2 H), 5.64 (s, 2 H), 4.58 (q, J = 7.0 Hz, 2 H), 2.09 (s, 3 H),1.39 (t, J = 7.0 Hz, 3 H). 341

556.57 557.1; 1.31 min (Method H) 13.08 (br s, 2 H), 9.31 (s, 1 H), 8.28(d, J = 8.2 Hz, 1 H), 8.12-8.24 (m, 1 H), 7.87 (d, J = 8.2 Hz, 1 H),7.60-7.80 (m, 3 H), 7.54 (d, J = 7.0 Hz, 1 H), 7.27-7.38 (m, 1 H),7.06-7.23 (m, 4 H), 6.97 (d, J = 8.2 Hz, 2 H), 5.66 (s, 2 H), 4.59 (q, J= 6.8 Hz, 2 H), 1.40 (t, J = 7.0 Hz, 3 H). 342

556.57 557.1; 1.32 min (Method H) 13.17 (br s, 2 H), 8.45 (s, 1 H), 8.00(dt, J = 8.3, 2.3 Hz, 2 H), 7.93 (d, J = 7.8 Hz, 1 H), 7.80-7.90 (m, 2H), 7.66 (d, J = 7.8 Hz, 1 H), 7.48-7.58 (m, 2 H), 7.31 (t, J = 7.4 Hz,1 H), 7.10-7.21 (m, 3 H), 6.97 (d, J = 7.8 Hz, 2 H), 5.64 (s, 2 H), 4.58(q, J = 7.0 Hz, 2 H), 1.38 (t, J = 7.0 Hz, 3 H).

Example 343:1-((5′-(Cyclohexyloxy)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 343a: Methyl2-ethoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-7-carboxylate

The title compound was prepared by the reaction of methyl2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (1.00 g, 4.54 mmol) with2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.44g, 4.77 mmol), in a similar fashion to that described for the synthesisof Intermediate 330a, and was obtained as a yellow solid (1.44 g, 3.31mmol, 72% yield). LC-MS (Method H): 1.42 min, [M+H]⁺=437.2; 41 NMR (400MHz, CDCl₃) δ ppm 7.73 (dd, J=8.0, 1.0 Hz, 1H), 7.67 (m, J=8.2 Hz, 2H),7.53 (dd, J=7.8, 1.2 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H), 6.96 (m, J=8.2 Hz,2H), 5.63 (s, 2H), 4.65 (q, J=7.0 Hz, 2H), 3.72 (s, 3H), 1.46 (t, J=7.0Hz, 3H), 1.31 (s, 12H). Intermediate 343b: Methyl1-02′-cyano-5′-(cyclohexyloxy)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

The title compound was prepared by the reaction of methyl2-ethoxy-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-benzo[d]imidazole-7-carboxylate(Intermediate 343a, 0.100 g, 0.229 mmol) with2-bromo-4-(cyclohexyloxy)benzonitrile (Intermediate 209a, 0.128 g, 0.458mmol), in a similar fashion to that described for the synthesis ofIntermediate 330b, and was obtained as an off-white solid (0.100 mg,0.196 mmol, 86% yield).). LC-MS (Method H): 1.58 min, [M+M]⁺=510.1; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 7.80 (d, J=8.6 Hz, 1H), 7.68-7.74 (m, 1H),7.41-7.56 (m, 4H), 7.32-7.40 (m, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.03-7.12(m, 3H), 7.02 (d, J=2.3 Hz, 1H), 5.57 (s, 2H), 4.62 (q, J=7.0 Hz, 2H),4.55 (dt, J=8.3, 4.3 Hz, 1H), 3.71 (s, 3H), 1.86-1.97 (m, 2H), 1.68 (dd,J=9.2, 3.3 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.31-1.59 (m, 4H), 1.14-1.30(m, 2H).

Example 343:1-((5′-(Cyclohexyloxy)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylicacid

The title compound was prepared from Intermediate 343b (0.050 g, 0.098mmol) according to the method described for the synthesis of Example 330and was obtained as a white solid (0.020 g, 0.037 mmol, 37% yield).).LC-MS (Method H): 1.36 min, [M+H]⁺=539.2; ¹H NMR (400 MHz, DMSO-d₆) δppm 13.16 (br s, 1H), 7.66 (d, J=7.8 Hz, 1H), 7.45-7.57 (m, 2H), 7.17(t, J=7.8 Hz, 1H), 7.10 (dd, J=8.6, 2.3 Hz, 1H), 6.98-7.04 (m, 2H),6.88-6.98 (m, 3H), 5.62 (s, 2H), 4.57 (q, J=7.0 Hz, 2H), 4.46-4.54 (m,1H), 1.86-2.00 (m, 2H), 1.62-1.77 (m, 2H), 1.32-1.55 (m, 4H), 1.38 (t,J=7.0 Hz, 3H), 1.21-1.31 (m, 2H).

Example 344:2-Ethoxy-1-((5′-(4-isopropyl-1H-1,2,3-triazol-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

Intermediate 344a: Methyl1-((5′-azido-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

The title compound was prepared by the reaction of methyl1-((2′-cyano-5′-fluoro-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate(Intermediate 330b, 0.100 g, 0.233 mmol) with sodium azide (0.030 g,0.466 mmol), using conditions similar to those reported for thesynthesis of Intermediate 330c, to afford a white solid (0.048 g, 0.11mmol, 45% yield).). LC-MS (Method H): 1.36 min, [M+H]⁺=539.2; ¹H NMR(400 MHz, DMSO-d₆) δ ppm 7.94 (d, J=8.2 Hz, 1H), 7.71 (dd, J=8.0, 1.0Hz, 1H), 7.52 (m, J=8.2 Hz, 2H), 7.47 (dd, J=7.8, 0.8 Hz, 1H), 7.28 (dd,J=8.2, 2.3 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.09(m, J=8.2 Hz, 2H), 5.58 (s, 2H), 4.62 (q, J=7.0 Hz, 2H), 3.70 (s, 3H),1.41 (t, J=7.0 Hz, 3H).

Intermediate 344b: Methyl1-((2′-cyano-5′-(4-isopropyl-1H-1,2,3-triazol-1-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate

To a mixture of Intermediate 344a (0.044 g, 0.097 mmol) in2-methylpropan-2-ol (2 mL) and H₂O (2 mL) was added 3-methylbut-1-yne(0.076 mL, 0.97 mmol), copper(II) sulfate pentahydrate (0.005 g, 0.019mmol) and sodium(R)-5-((S)-1,2-dihydroxyethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-olate(0.004 g, 0.019 mmol) and the mixture was stirred at RT for 18 h andthen at 65° C. for 24 h. To the resulting mixture was added anotherportion of copper(II) sulfate pentahydrate (0.005 g, 0.019 mmol) andsodium(R)-5-((S)-1,2-dihydroxyethyl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-olate(0.004 g, 0.019 mmol) and heating was continued at 65° C. for anadditional 24 h. To the cooled mixture was added H₂O (3 mL), brine (2mL) and tert-butylmethyl ether (10 mL). The organic phase was separatedand the aqueous phase was re-extracted with tert-butylmethyl ether (5mL). The combined organic extract was evaporated and residue was takenup in DMSO (3 mL) and the mixture was filtered. The filtrate wassubmitted to reverse phase HPLC purification (Method F, using formicacid as modifier) to afford the title compound as a white solid (0.035g, 0.067 mmol, 69% yield). LC-MS (Method H): 1.37 min, [M+H]⁺=521.2; ¹HNMR (400 MHz, DMSO-d₆) δ ppm 8.83 (s, 1H), 8.11-8.20 (m, 2H), 8.09 (d,J=1.6 Hz, 1H), 7.72 (dd, J=7.8, 1.2 Hz, 1H), 7.62 (m, J=8.2 Hz, 2H),7.48 (dd, J=7.8, 0.8 Hz, 1H), 7.21 (t, J=7.8 Hz, 1H), 7.13 (m, J=8.2 Hz,2H), 5.60 (s, 2H), 4.63 (q, J=7.0 Hz, 2H), 3.73 (s, 3H), 3.06 (dt,J=13.9, 6.7 Hz, 1H), 1.42 (t, J=7.0 Hz, 3H), 1.29 (d, J=7.0 Hz, 6H).

Example 344:2-Ethoxy-1-((5′-(4-isopropyl-1H-1,2,3-triazol-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylicacid

The reaction of Intermediate 344b (0.035 g, 0.061 mmol) according to themethod described for the synthesis of Example 330 provided the titlecompound as a white solid (0.015 g, 0.027 mmol, 44% yield). LC-MS(Method H): 1.27 min, [M+H]⁺=550.2; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.78(s, 1H), 8.10 (d, J=7.8 Hz, 1H), 7.96 (br s, 1H), 7.85 (d, J=8.6 Hz,1H), 7.66 (d, J=7.8 Hz, 1H), 7.54 (d, J=7.0 Hz, 1H), 7.17 (t, J=7.8 Hz,1H), 7.11 (m, J=7.8 Hz, 2H), 6.96 (m, J=7.4 Hz, 2H), 5.65 (br s, 2H),4.58 (q, J=7.0 Hz, 2H), 3.05 (tt, J=13.8, 6.7 Hz, 1H), 1.39 (t, J=7.0Hz, 3H), 1.29 (d, J=7.0 Hz, 6H).

Example 345:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-1H-imidazole-5-carboxylicacid, TFA salt

Intermediate 345a:2-butyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carbaldehyde

2-Butyl-4-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carbaldehyde(035a 2 g, 4.97 mmol) was dissolved in MeOH (100 mL). KOAc (0.585 g,5.96 mmol) was added followed by Degussa Pd—C (0.264 g, 0.248 mmol). Thereaction mixture was evacuated and backfilled with 1 atm of hydrogen andwas stirred at RT for 1 hour and 45 min. The reaction mixture was thenevacuated and backfilled with N₂ and filtered through a celite pad whichwas washed with MeOH. The MeOH was concentrated in vacuo. The residuewas then suspended in EtOAc and extracted with H₂O 2×, brine 1×, driedwith sodium sulfate, filtered and concentrated to yield the titlecompound (345a, 3.8 g, 9.60 mmol, 97% yield). LC-MS (Method A2): 0.84min, [M+H]⁺=369.15; ¹H NMR (500 MHz, CDCl₃) δ 9.79-9.76 (m, 1H), 9.69(s, 1H), 7.81 (s, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.02 (d, J=8.0 Hz, 2H),5.62 (s, 2H), 5.60-5.59 (m, 1H), 2.68-2.63 (m, 2H), 1.76-1.65 (m, 2H),1.40-1.37 (m, 2H), 1.37-1.33 (m, 12H), 0.94-0.85 (m, 3H).

Intermediate 345b:4″-((2-butyl-5-formyl-1H-imidazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

2-butyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carbaldehyde(345a, 1200 mg, 3.26 mmol), 3-chloro-[1,1′-biphenyl]-4-carbonitrile (766mg, 3.58 mmol) and 2nd generation xphos precatalyst (128 mg, 0.163 mmol)were dissolved in dioxane (16 mL) followed by 2 M K₃PO₄ (2 M aq) (3.3mL, 6.52 mmol). The reaction mixture was evacuated and backfilled withN₂ (3×) and then heated at 85° C. for 15 h. The reaction mixture wasthen concentrated onto celite and purified by ISCO (0-100%EtOAc/Hexanes) to afford the title compound (345b, 0.8 g, 1.907 mmol,52.3% yield). LC-MS: MS (ESI) m/z: 420.1 (M+H)+; ¹H NMR (500 MHz, CDCl₃)δ 9.72 (s, 1H), 7.85 (t, J=4.0 Hz, 2H), 7.74-7.57 (m, 6H), 7.55-7.43 (m,3H), 7.19 (d, J=8.3 Hz, 2H), 5.68 (s, 2H), 2.80-2.70 (m, 2H), 1.77 (t,J=7.7 Hz, 2H), 1.47-1.35 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).

Intermediate 345c:2-butyl-1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

4″-((2-butyl-5-formyl-1H-imidazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile(345b, 1.5 g, 3.58 mmol) and 2M 2-methylbut-2-ene in THF (7.15 mL, 14.30mmol) were dissolved in 1-butanol (20 mL). Water (20 mL) was addedfollowed by sodium dihydrogen phosphate (1.287 g, 10.73 mmol) and sodiumchlorite (0.970 g, 10.73 mmol). The reaction mixture was allowed to stirat RT for 15 h. The reaction mixture was then cooled to 0° C. andquenched with 10% aq. sodium sulfite (31.5 g, 25.03 mmol). The reactionmixture was allowed to stir at RT for 10 min and was then extracted withEtOAc 3×. The combined organic layer was then washed with brine, driedwith sodium sulfate, filtered and concentrated to yield2-butyl-1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (345c, 1.17 g, 2.176 mmol, 60.9% yield). LC-MS (Method A2): 0.84min, [M+H]⁺=436.10;

Example 345:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-1H-imidazole-5-carboxylicacid, TFA salt

To a small vial containing2-butyl-1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (345c, 485 mg, 0.902 mmol) was added dibutyltin oxide (225 mg,0.902 mmol) and toluene (20 mL) followed by TMS-N₃ (0.599 mL, 4.51mmol). The reaction mixture was sealed and heated at 100° C. for 18 h.The reaction mixture was then diluted with hexanes and celite was added.The mixture was filtered and washed with hexanes. The celite was thenpurified using reverse phase ISCO (0-100% B. A=H₂O/ACN/TFA 90:10:0.1.B=ACN/H₂O/TFA 90:10:0.1) to afford the title compound (Example 345, 834mg, 1.196 mmol, 66.3% yield). LC-MS (Method A4): 1.599 min,[M+H]⁺=479.0; ¹H NMR (500 MHz, DMSO-d₆) δ 7.75 (d, J=7.6 Hz, 2H), 7.69(q, J=7.9 Hz, 2H), 7.58 (s, 2H), 7.48 (t, J=7.5 Hz, 2H), 7.42-7.35 (m,1H), 7.16 (d, J=7.9 Hz, 2H), 6.89 (d, J=7.9 Hz, 2H), 5.59 (s, 2H), 2.58(t, J=7.5 Hz, 2H), 1.54 (quin, J=7.5 Hz, 2H), 1.36-1.18 (m, 2H), 0.81(t, J=7.3 Hz, 3H).

Example 346:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-N-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-imidazole-5-carboxamide

(1-methyl-1H-pyrazol-4-yl)methanamine (116 mg, 1.041 mmol),1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-1H-imidazole-5-carboxylicacid (Example 345, 200 mg, 0.347 mmol), and Hunig's Base (224 mg, 1.734mmol) were dissolved in DMF (5 mL). HATU (264 mg, 0.694 mmol) was addedand the reaction mixture was allowed to stir at RT for 18 h. Thereaction mixture was then filtered and purified via preparative HPLC(XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂Owith 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc;Gradient: 13-53% B over 20 mm, then a 6-minute hold at 100% B; Flow: 20mL/min) to afford the title compound (Example 346, 128.1 mg, 0.217 mmol,62.7% yield). LC-MS (Method A4): 1.542 min, [M+H]⁺=572.4; ¹H NMR (500MHz, DMSO-d₆) δ 8.46 (br t, J=5.7 Hz, 1H), 7.82-7.69 (m, 4H), 7.68-7.62(m, 1H), 7.56-7.46 (m, 4H), 7.45-7.37 (m, 1H), 7.28 (s, 1H), 7.22-7.12(m, J=8.1 Hz, 2H), 7.02-6.87 (m, J=8.1 Hz, 2H), 5.63 (s, 2H), 4.22 (d,J=5.8 Hz, 2H), 2.59-2.53 (m, 5H), 1.56 (quin, J=7.5 Hz, 2H), 1.34-1.23(m, 2H), 0.84 (t, J=7.4 Hz, 3H).

The following examples have been similarly prepared from Example 345 asdescribed above for Example 346.

LC-MS m/z [M + H]⁺; RT (min) ¹H NMR (500 MHz, Ex Structure MW (MethodA4) DMSO-d₆) δ ppm 347

531.664 532.1; 1.71  ¹H NMR (500 MHz, DMSO- d₆) δ 8.60 (s, 1H), 8.33 (brd, J = 2.4 Hz, 1H), 7.93 (br d, J = 7.9 Hz, 1H), 7.84 (s, 1H), 7.81-7.73(m, 2H), 7.27-7.11 (m, J = 7.9 Hz, 2H), 7.04-6.94 (m, J = 7.9 Hz, 2H),5.60 (s, 2H), 3.92 (s, 3H), 2.69-2.57 (m, 2H), 1.59-1.44 (m, 2H), 1.33-1.15 (m, 2H), 0.81 (br t, J = 7.2 Hz, 3H). 348

521.625 522.5; 1.424 ¹H NMR (500 MHz, DMSO- d₆) δ 8.25 (br. s., 1H),7.82- 7.72 (m, 3H), 7.67 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.54 (s,1H), 7.48 (t, J = 7.6 Hz, 2H), 7.40 (d, J = 7.4 Hz, 1H), 7.12 (d, J =7.8 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 5.60 (s, 2H), 3.44 (t, J = 6.1Hz, 2H), 3.23 (q, J = 6.0 Hz, 2H), 2.53 (br. s., 2H), 1.57-1.45 (m, 2H),1.29-1.15 (m, 2H), 0.79 (t, J = 7.3 Hz, 3H). 349

574.71  575.5; 1.690 ¹H NMR (500 MHz, DMSO- d₆) δ 8.08 (br s, 1H), 7.86-7.75 (m, 3H), 7.75-7.67 (m, 2H), 7.49 (br t, J = 7.5 Hz, 2H), 7.45-7.38(m, 1H), 7.15 (br d, J = 7.7 Hz, 2H), 6.97 (br d, J = 7.9 Hz, 2H), 6.75(s, 1H), 5.68 (br s, 2H), 2.64-2.55 (m, 2H), 2.27 (s, 3H), 1.51 (br d, J= 6.5 Hz, 2H), 1.25 (br d, J = 6.9 Hz, 2H), 0.80 (br t, J = 6.9 Hz, 3H).350

563.706 564.5; 1.440 ¹H NMR (500 MHz, DMSO- d₆) δ 8.22 (br s, 1H), 7.87-7.76 (m, 3H), 7.72 (br d, J = 8.2 Hz, 2H), 7.55-7.46 (m, 3H), 7.46-7.39(m, 1H), 7.13 (br d, J = 8.0 Hz, 2H), 6.95 (br d, J = 8.0 Hz, 2H), 5.62(br s, 2H), 3.32-3.16 (m, 2H), 2.57-2.55 (m, 2H), 1.63-1.52 (m, 2H),1.48 (br s, 2H), 1.23 (br d, J = 7.2 Hz, 2H), 1.09 (s, 6H), 0.85- 0.74(m, 3H). 351

571.729 572.5; 1.901 ¹H NMR (500 MHz, DMSO- d₆) δ 8.57-8.36 (m, 1H),7.84 (br d, J = 8.0 Hz, 1H), 7.80- 7.68 (m, 4H), 7.57-7.47 (m, 3H),7.46-7.38 (m, 1H), 7.19-7.03 (m, J = 8.0 Hz, 2H), 6.99-6.88 (m, J = 8.0Hz, 2H), 5.58 (s, 2H), 4.23- 4.05 (m, 1H), 2.59-2.54 (m, 2H), 2.31-2.18(m, 2H), 2.00-1.83 (m, 6H), 1.75 (q, J = 7.7 Hz, 2H), 1.45 (quin, J =7.5 Hz, 2H), 1.28-1.13 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H). 352

533.68  534.6; 1.675 ¹H NMR (500 MHz, DMSO- d₆) δ 7.85-7.75 (m, 3H),7.75-7.67 (m, 2H), 7.63 (br s, 1H), 7.54-7.45 (m, 3H), 7.45-7.39 (m,1H), 7.17-7.09 (m, J = 7.8 Hz, 2H), 7.05- 6.94 (m, J = 7.9 Hz, 2H), 5.55(s, 2H), 2.58-2.52 (m, 2H), 1.46 (br d, J = 7.0 Hz, 2H), 1.29 (s, 9H),1.22 (br d, J = 7.3 Hz, 2H), 0.78 (br t, J = 7.3 Hz, 3H). 353

554.658 555;   1.496 [NEED NMR] 354

559.718 560;   1.520 ¹H NMR (500 MHz, DMSO- d₆) δ 8.50-8.30 (m, 1H),7.84 (br d, J = 8.0 Hz, 1H), 7.80-7.68 (m, 4H), 7.57- 7.47 (m, 3H),7.46-7.38 (m, 1H), 7.18-7.05 (m, J = 8.0 Hz, 2H), 6.99-6.88 (m, J = 8.0Hz, 2H), 5.58 (s, 2H), 4.32-4.06 (m, J = 7.9 Hz, 1H), 2.59-2.54 (m, 2H),2.24 (br s, 2H), 2.04-1.89 (m, 4H), 1.85 (br d, J = 7.5 Hz, 2H), 1.75(br d, J = 7.1 Hz, 2H), 1.45 (br d, J = 7.4 Hz, 2H), 1.20 (br d, J = 7.4Hz, 2H), 0.77 (t, J = 7.3 Hz, 3H). 355

569.673 570.1; 1.571 ¹H NMR (500 MHz, DMSO- d₆) δ 9.08 (br d, J = 4.6Hz, 2H), 7.94-7.74 (m, 3H), 7.71 (br d, J = 8.0 Hz, 1H), 7.68- 7.61 (m,3H), 7.54-7.46 (m, 3H), 7.46-7.37 (m, 1H), 7.13 (br d, J = 7.7 Hz, 2H),6.93 (br d, J = 8.0 Hz, 2H), 5.60 (s, 2H), 4.66 (br d, J = 5.7 Hz, 2H),2.56 (br s, 2H), 1.57-1.44 (m, 2H), 1.31-1.19 (m, 2H), 0.80 (br t, J =7.3 Hz, 3H). 356

574.71  575.2; 1.676 ¹H NMR (500 MHz, DMSO- d₆) δ 9.23 (br s, 1H), 7.78(br d, J = 8.6 Hz, 3H), 7.74- 7.63 (m, 4H), 7.57 (br s, 1H), 7.53-7.40(m, 3H), 7.21-7.06 (m, J = 7.8 Hz, 2H), 7.01- 6.91 (m, J = 8.0 Hz, 2H),5.64 (s, 2H), 4.66 (br d, J = 5.9 Hz, 2H), 2.61-2.56 (m, 2H), 1.67-1.40(m, 2H), 1.36-1.08 (m, J = 7.2 Hz, 2H), 0.80 (br t, J = 7.2 Hz, 3H). 357

545.29  546.1; 1.853 ¹H NMR (500 MHz, DMSO- d₆) δ 8.30 (br s, 1H), 7.85(br d, J = 7.9 Hz, 1H), 7.79 (br d, J = 7.4 Hz, 2H), 7.76- 7.69 (m, 2H),7.56-7.47 (m, 3H), 7.47-7.40 (m, 1H), 7.17-7.09 (m, J = 7.9 Hz, 2H),7.01-6.91 (m, J = 7.9 Hz, 2H), 5.62 (s, 2H), 3.29- 3.16 (m, 2H),2.58-2.53 (m, 2H), 1.55-1.43 (m, 2H), 1.35 (q, J = 6.8 Hz, 2H),1.29-1.17 (m, 2H), 0.80 (br t, J = 7.3 Hz, 3H), 0.65 (br s, 1H), 0.35(br d, J = 7.7 Hz, 2H), 0.00 (br d, J = 3.6 Hz, 2H). 358

533.636 534;   1.622 ¹H NMR (500 MHz, DMSO- d₆) δ 8.94 (br s, 1H), 7.79-7.63 (m, 6H), 7.59 (s, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.44-7.35 (m, 1H),7.22- 7.05 (m, J = 7.9 Hz, 2H), 6.97-6.80 (m, J = 8.0 Hz, 2H), 5.58 (s,2H), 5.02-4.85 (m, 1H), 4.72 (t, J = 6.9 Hz, 2H), 4.52 (t, J = 6.3 Hz,2H), 2.57-2.53 (m, 2H), 1.60-1.44 (m, 2H), 1.32- 1.18 (m, 2H), 0.81 (brt, J = 7.3 Hz, 3H). 359

569.7   570;   1.79  ¹H NMR (500 MHz, DMSO- d₆) δ 9.00 (br s, 1H), 8.56(br s, 1H), 8.52 (s, 1H), 8.49 (br s, 1H), 7.89-7.71 (m, 5H), 7.66 (s,1H), 7.52 (br t, J = 7.4 Hz, 2H), 7.48-7.39 (m, 1H), 7.14 (br d, J = 7.9Hz, 2H), 6.97 (br d, J = 7.7 Hz, 2H), 5.62 (br s, 2H), 4.53 (br d, J =5.5 Hz, 2H), 2.61-2.54 (m, 2H), 1.60- 1.44 (m, 2H), 1.37-1.21 (m, 2H),0.81 (br t, J = 7.0 Hz, 3H). 360

577.733 578.6; 1.857 ¹H NMR (500 MHz, DMSO- d₆) δ 8.11 (br s, 1H), 7.83-7.73 (m, 3H), 7.73-7.63 (m, 2H), 7.56-7.46 (m, 3H), 7.46-7.38 (m, 1H),7.11 (br d, J = 7.6 Hz, 2H), 6.94 (br d, J = 7.9 Hz, 2H), 5.59 (s, 2H),3.24-3.14 (m, 3H), 3.06 (br d, J = 6.2 Hz, 2H), 3.00 (s, 2H), 2.57-2.53(m, 2H), 1.54-1.42 (m, 2H), 1.32-1.14 (m, 2H), 0.82- 0.74 (m, 9H). 361

563.706 564.2; 1.823 ¹H NMR (500 MHz, DMSO- d₆) δ 7.94-7.75 (m, 3H),7.70 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.53-7.45 (m, 4H), 7.45-7.38 (m,1H), 7.13 (br d, J = 7.7 Hz, 2H), 6.99 (br d, J = 7.9 Hz, 2H), 5.55 (s,2H), 3.61-3.40 (m, 2H), 3.24-3.14 (m, 3H), 2.58- 2.52 (m, 2H), 1.54-1.37(m, 2H), 1.29-1.20 (m, 8H), 0.80 (br t, J = 7.2 Hz, 3H). 362

573.745 574.0; 2.001 ¹H NMR (500 MHz, DMSO- d₆) δ 8.09 (br s, 1H), 7.86(br d, J = 8.0 Hz, 1H), 7.80 (br d, J = 7.3 Hz, 2H), 7.77- 7.70 (m, 2H),7.57-7.47 (m, 3H), 7.47-7.40 (m, 1H), 7.21-7.08 (m, J = 7.7 Hz, 2H),7.02-6.93 (m, J = 7.7 Hz, 2H), 5.61 (br s, 2H), 2.65-2.53 (m, 2H), 1.76(br s, 2H), 1.61 (br s, 2H), 1.57- 1.44 (m, 9H), 1.43-1.33 (m, 2H), 1.24(br d, J = 7.2 Hz, 2H), 0.80 (br t, J = 7.2 Hz, 3H). 363

600.727 601.0; 1.865 ¹H NMR (500 MHz, DMSO- d₆) δ 8.95 (br s, 1H), 7.86(br d, J = 8.0 Hz, 1H), 7.80 (br d, J = 7.5 Hz, 2H), 7.77- 7.71 (m, 2H),7.65 (s, 1H), 7.51 (t, J = 7.1 Hz, 2H), 7.47-7.39 (m, 1H), 7.22-7.05 (m,J = 7.8 Hz, 2H), 7.02- 6.93 (m, J = 7.8 Hz, 2H), 6.22 (br s, 1H), 5.63(br s, 2H), 4.47 (br d, J = 5.5 Hz, 2H), 3.01-2.82 (m, 1H), 2.59-2.53(m, 2H), 1.60- 1.41 (m, 2H), 1.31-1.18 (m, 2H), 1.14 (br d, J = 6.8 Hz,6H), 0.80 (br t, J = 7.2 Hz, 3H). 364

541.607 542.5; 1.713 ¹H NMR (500 MHz, DMSO- d₆) δ 8.66 (br s, 1H), 7.94-7.75 (m, 3H), 7.73-7.62 (m, 3H), 7.49 (t, J = 7.5 Hz, 2H), 7.45-7.37 (m,1H), 7.20-7.07 (m, J = 7.9 Hz, 2H), 6.99- 6.90 (m, J = 7.9 Hz, 2H),6.26-5.80 (m, 1H), 5.61 (s, 2H), 3.80-3.69 (m, 2H), 2.57-2.53 (m, 2H),1.56- 1.46 (m, 2H), 1.30-1.18 (m, 2H), 0.80 (br t, J = 7.2 Hz, 3H). 365

531.664 532.5; 1.777 ¹H NMR (500 MHz, DMSO- d₆) δ 8.23 (br s, 1H), 7.78-7.59 (m, 3H), 7.59-7.50 (m, 2H), 7.41-7.30 (m, 3H), 7.30-7.22 (m, 1H),7.04-6.91 (m, J = 7.9 Hz, 2H), 6.85- 6.75 (m, J = 8.0 Hz, 2H), 5.46 (s,2H), 2.89 (br t, J = 6.2 Hz, 2H), 2.42- 2.37 (m, 2H), 1.41-1.26 (m, 2H),1.13-1.02 (m, 2H), 0.78 (br d, J = 6.8 Hz, 1H), 0.64 (br t, J = 7.3 Hz,3H), 0.28-0.17 (m, 2H), 0.00 (br d, J = 4.5 Hz, 2H). 366

547.707 548.2; 1.925 ¹H NMR (500 MHz, DMSO- d₆) δ 8.24 (br s, 1H), 7.86-7.76 (m, 3H), 7.76-7.68 (m, 2H), 7.55-7.46 (m, 3H), 7.46-7.39 (m, 1H),7.17-7.09 (m, J = 8.0 Hz, 2H), 7.00- 6.92 (m, J = 7.9 Hz, 2H), 5.62 (s,2H), 3.18 (q, J = 6.5 Hz, 2H), 2.56-2.52 (m, 2H), 1.58-1.44 (m, 3H),1.34 (q, J = 6.9 Hz, 2H), 1.29-1.18 (m, 2H), 1.00 (d, J = 6.3 Hz, 1H),0.90-0.77 (m, 9H). 367

563.706 564.2; 1.925 ¹H NMR (500 MHz, DMSO- d₆) δ 8.32 (br d, J = 4.8Hz, 1H), 7.81-7.73 (m, 3H), 7.70 (br d, J = 7.9 Hz, 1H), 7.64 (s, 1H),7.55-7.46 (m, 3H), 7.45-7.37 (m, 1H), 7.12 (br d, J = 7.7 Hz, 2H), 6.93(br d, J = 8.0 Hz, 2H), 5.61 (br s, 2H), 3.60-3.46 (m, 1H), 3.44-3.35(m, 2H), 3.32-3.23 (m, 2H), 2.57-2.55 (m, 2H), 1.56-1.42 (m, 2H),1.29-1.14 (m, 2H), 1.08-0.97 (m, 6H), 0.79 (br t, J = 7.2 Hz, 3H). 368

533.68  534.5; 1.826 ¹H NMR (500 MHz, DMSO- d₆) δ 8.23 (br s, 1H), 7.78-7.59 (m, 3H), 7.59-7.50 (m, 2H), 7.41-7.30 (m, 3H), 7.30-7.22 (m, 1H),7.04-6.91 (m, J = 7.9 Hz, 2H), 6.85- 6.75 (m, J = 8.0 Hz, 2H), 5.46 (s,2H), 3.19-3.06 (m, 1H), 2.89 (br t, J = 6.2 Hz, 2H), 2.39 (s, 2H),1.41-1.26 (m, 2H), 1.13-1.02 (m, 2H), 0.89-0.70 (m, 2H), 0.64 (br t, J =7.3 Hz, 3H), 0.23 (br d, J = 7.4 Hz, 2H), 0.00 (br d, J = 4.5 Hz, 2H).369

559.718 560.5; 1.923 ¹H NMR (500 MHz, DMSO- d₆) δ 7.97 (br d, J = 7.7Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.68-7.55 (m, 4H), 7.43-7.34 (m, 3H),7.34- 7.26 (m, 1H), 7.05-6.94 (m, J = 7.9 Hz, 2H), 6.90-6.82 (m, J = 8.1Hz, 2H), 5.46 (s, 2H), 3.16-3.01 (m, 1H), 2.51-2.45 (m, 2H), 1.51- 1.31(m, 4H), 1.19-1.02 (m, 2H), 0.78-0.63 (m, 7H), 0.36-0.23 (m, 1H), 0.15(br dd, J = 8.0, 4.0 Hz, 1H), 0.09-0.05 (m, 2H). 370

517.637 518.5; 1.535 ¹H NMR (500 MHz, DMSO- d₆) δ 7.74 (br s, 4H), 7.59(br s, 1H), 7.48 (br t, J = 7.4 Hz, 2H), 7.44-7.26 (m, 2H), 7.12 (br s,2H), 6.87 (br s, 2H), 5.67-5.50 (m, 2H), 4.38-4.16 (m, 2H), 4.10- 3.92(m, 2H), 2.57-2.53 (m, 2H), 2.31-2.18 (m, 2H), 1.61-1.40 (m, 2H), 1.37-1.17 (m, 2H), 0.86-0.73 (m, 3H). 371

568.685 569.5; 1.377 ¹H NMR (500 MHz, DMSO- d₆) δ 8.95 (br s, 1H), 8.46(br s, 1H), 7.80-7.62 (m, 7H), 7.49 (t, J = 7.2 Hz, 2H), 7.45-7.37 (m,1H), 7.25-7.17 (m, 2H), 7.14 (br d, J = 7.7 Hz, 2H), 6.94 (br d, J = 7.9Hz, 2H), 5.62 (br s, 2H), 4.47 (br d, J = 5.8 Hz, 2H), 2.59-2.53 (m,2H), 1.56-1.47 (m, 2H), 1.26 (br d, J = 7.0 Hz, 2H), 0.85-0.76 (m, 3H).372

519.653 520.5; 1.656 ¹H NMR (500 MHz, DMSO- d₆) δ 8.28 (br s, 1H), 7.79-7.71 (m, 3H), 7.71-7.65 (m, 1H), 7.61 (s, 1H), 7.53-7.46 (m, 3H),7.44-7.35 (m, 1H), 7.19-7.07 (m, J = 7.8 Hz, 2H), 6.95-6.88 (m, J = 7.9Hz, 2H), 5.60 (br s, 2H), 3.19-3.05 (m, 2H), 2.57- 2.52 (m, 2H),1.56-1.40 (m, 4H), 1.31-1.17 (m, 2H), 0.87-0.75 (m, 6H). 373

547.707 548.6; 1.806 ¹H NMR (500 MHz, DMSO- d₆) δ 8.20 (br s, 1H), 7.75(br d, J = 7.8 Hz, 3H), 7.68 (br d, J = 8.0 Hz, 1H), 7.60 (br s, 1H),7.58-7.53 (m, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.43-7.38 (m, 1H), 7.12 (brd, J = 7.7 Hz, 2H), 6.92 (br d, J = 7.8 Hz, 2H), 5.58 (br s, 2H), 2.99(br d, J = 6.1 Hz, 2H), 2.58-2.53 (m, 2H), 1.55-1.45 (m, 2H), 1.29- 1.20(m, 2H), 0.85-0.76 (m, 12H). 374

535.652 536.3; 1.703 ¹H NMR (500 MHz, DMSO- d₆) δ 8.35 (br s, 1H), 7.93-7.74 (m, 3H), 7.73-7.64 (m, 2H), 7.57-7.45 (m, 3H), 7.45-7.36 (m, 1H),7.19-7.05 (m, J = 7.9 Hz, 2H), 6.99- 6.90 (m, J = 8.0 Hz, 2H), 5.61 (s,2H), 3.43-3.24 (m, 4H), 3.21 (s, 3H), 2.57-2.52 (m, 2H), 1.56-1.43 (m,2H), 1.30-1.14 (m, 2H), 0.78 (t, J = 7.3 Hz, 3H) 375

568.685 569.5; 1.519 ¹H NMR (500 MHz, DMSO- d₆) δ 8.67 (br s, 1H), 8.60(br d, J = 5.7 Hz, 1H), 8.27 (br d, J = 6.3 Hz, 1H), 8.20 (s, 1H), 7.87(br d, J = 7.9 Hz, 1H), 7.83-7.70 (m, 4H), 7.51 (t, J = 7.1 Hz, 2H),7.47-7.41 (m, 1H), 7.29 (br s, 1H), 7.22-7.14 (m, J = 8.0 Hz, 2H),7.13-7.04 (m, J = 8.0 Hz, 2H), 5.68 (s, 2H), 2.80-2.68 (m, 2H), 2.48-2.36 (m, 3H), 1.60-1.45 (m, 2H), 1.32-1.14 (m, 2H), 0.82 (br t, J = 7.3Hz, 3H). 376

569.673 570.5; 1.644 ¹H NMR (500 MHz, DMSO- d₆) δ 8.37 (s, 1H), 8.16 (d,J = 8.9 Hz, 1H), 7.87 (br d, J = 8.2 Hz, 1H), 7.83-7.71 (m, 5H), 7.60(d, J = 9.2 Hz, 1H), 7.51 (t, J = 6.9 Hz, 2H), 7.45 (br t, J = 7.3 Hz,1H), 7.22-7.15 (m, 2H), 7.14-7.02 (m, 2H), 5.76 (s, 2H), 2.84- 2.66 (m,2H), 2.59 (s, 3H), 1.60-1.46 (m, 2H), 1.36-1.15 (m, 2H), 0.82 (br t, J =7.2 Hz, 3H). 377

545.691 546.4; 1.860 ¹H NMR (500 MHz, DMSO- d₆) δ 8.14 (br d, J = 7.1Hz, 1H), 7.87-7.76 (m, 3H), 7.76-7.68 (m, 2H), 7.58-7.46 (m, 3H),7.46-7.39 (m, 1H), 7.18-7.10 (m, J = 7.9 Hz, 2H), 7.00-6.94 (m, J = 8.0Hz, 2H), 5.60 (s, 2H), 4.11 (br d, J = 7.0 Hz, 1H), 2.55 (s, 2H),1.91-1.75 (m, 2H), 1.70-1.57 (m, 2H), 1.55- 1.39 (m, 6H), 1.31-1.15 (m,2H), 0.79 (t, J = 7.3 Hz, 3H). 378

545.691 546.1; 1.643 ¹H NMR (500 MHz, DMSO- d₆) δ 7.80-7.63 (m, 5H),7.57 (s, 1H), 7.49 (br t, J = 7.6 Hz, 2H), 7.45-7.36 (m, 1H), 7.15 (brd, J = 7.9 Hz, 2H), 7.04 (s, 1H), 6.93 (br d, J = 8.1 Hz, 2H), 5.29 (s,2H), 3.57-3.36 (m, 3H), 2.66 (br t, J = 7.7 Hz, 2H), 1.63-1.53 (m, 2H),1.49 (br s, 2H), 1.38-1.16 (m, 6H), 0.85 (t, J = 7.3 Hz, 3H). 379

505.626 506.1; 1.587 ¹H NMR (500 MHz, DMSO- d₆) δ 8.29 (br s, 1H), 7.83-7.74 (m, 3H), 7.70 (d, J = 8.0 Hz, 1H), 7.68 (s, 1H), 7.55- 7.46 (m,3H), 7.45-7.37 (m, 1H), 7.19-7.08 (m, J = 7.9 Hz, 2H), 6.98-6.90 (m, J =8.0 Hz, 2H), 5.62 (s, 2H), 3.65 (br s, 2H), 3.24-3.13 (m, 2H), 1.55-1.43(m, 2H), 1.31-1.16 (m, 2H), 1.06 (t, J = 7.2 Hz, 3H), 0.79 (t, J = 7.3Hz, 3H). 380

531.664 532.2; 1.701 ¹H NMR (500 MHz, DMSO- d₆) δ 8.45 (br d, J = 7.2Hz, 1H), 7.84-7.75 (m, 3H), 7.75-7.67 (m, 2H), 7.59 (s, 1H), 7.50 (t, J= 7.6 Hz, 2H), 7.46-7.38 (m, 1H), 7.18- 7.09 (m, J = 7.8 Hz, 2H),6.98-6.89 (m, J = 8.0 Hz, 2H), 5.60 (s, 2H), 4.31 (br d, J = 8.1 Hz,1H), 2.57-2.53 (m, 2H), 2.22-2.10 (m, 2H), 1.99 (br t, J = 9.7 Hz, 2H),1.69-1.55 (m, 2H), 1.55- 1.43 (m, 2H), 1.30-1.15 (m, 2H), 0.79 (t, J =7.3 Hz, 3H).

Example 381:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-N,N-dimethyl-1H-imidazole-5-carboxamide

Example 381 was synthesized from Example 384 and dimethyl amine using asimilar procedure as was used for the synthesis of Example 346, however,T3P was used in place of HATU as the coupling reagent. LC-MS (MethodA4): 1.976 min, [M+H]⁺=540.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.87-7.69 (m,4H), 7.64 (s, 1H), 7.54-7.46 (m, 2H), 7.45-7.37 (m, 1H), 7.18 (d, J=7.9Hz, 2H), 6.97 (d, J=7.9 Hz, 2H), 5.15 (br. s., 2H), 2.81 (s, 3H),2.71-2.67 (m, 2H), 2.65 (br. s., 3H), 1.67-1.54 (m, 2H), 1.40-1.26 (m,2H), 0.87 (t, J=7.3 Hz, 3H).

Example 382:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-N-methyl-1H-imidazole-5-carboxamide

Example 382 was synthesized from 2M methanamine in MeOH and Example 345using the same procedure described for Example 381 to give the titlecompound (Example 382, 2.9 mg, 5.90 μmol, 7.43% yield). MS (ESI) m/z(M+H)⁺=492.1. ¹H NMR (500 MHz, DMSO-d₆) δ 8.21 (d, J=4.6 Hz, 1H),7.81-7.74 (m, 3H), 7.73-7.68 (m, 1H), 7.65 (s, 1H), 7.55-7.45 (m, 3H),7.41 (d, J=7.3 Hz, 1H), 7.15 (d, J=7.9 Hz, 2H), 6.91 (d, J=7.9 Hz, 2H),5.63 (s, 2H), 2.70 (d, J=4.6 Hz, 3H), 2.53 (br. s., 2H), 1.59-1.46 (m,2H), 1.31-1.18 (m, 2H), 0.81 (t, J=7.3 Hz, 3H). LC-MS retention time(Method A4): 1.536 min

Example 383:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-N,N-dimethyl-1H-imidazole-5-carboxamide

Example 383 was synthsized from 2M dimethylamine in MeOH and Example 345using the same procedure described for Example 381 to give the titlecompound (Example 383, 6.2 mg, 0.012 mmol, 15.44% yield). MS (ESI) m/z(M+H)⁺=506.1. ¹H NMR (500 MHz, DMSO-d₆) δ 7.78 (d, J=7.3 Hz, 3H), 7.72(d, J=7.9 Hz, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.53-7.46 (m, 2H),7.44-7.36 (m, 1H), 7.20 (d, J=7.9 Hz, 2H), 7.10 (d, J=7.9 Hz, 2H), 5.19(s, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.61-1.48 (m, 2H), 1.36-1.26 (m, 2H),0.84 (t, J=7.3 Hz, 3H). LC-MS retention time (Method A4): 1.541 min

Example 384:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid

Intermediate 384a:4′-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-chloro-[1,1′-biphenyl]-2-carbonitrile

To a microwave vial containing2-butyl-4-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carbaldehyde(035a, 1.4 g, 3.48 mmol), 4-chloro-2-iodobenzonitrile (1.007 g, 3.82mmol) and 2 M K₃PO₄ (2 M aq) (3.48 ml, 6.95 mmol) was added 4:1toluene/ethanol (11.59 ml) followed by PdCl₂(dppf) (0.382 g, 0.521mmol). The reaction mixture was sparged with N₂ for 2 min before beingsealed and heated at 120° C. for 30 min in the microwave. The reactionmixture was concentrated onto celite and purified by ISCO (0-100%EtOAc/Hexanes) to afford the title compound (384a, 1.1 g, 2.67 mmol, 77%yield). LC-MS: MS (ESI) m/z: 412.00 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ9.80 (s, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.51 (d,J=1.9 Hz, 1H), 7.49-7.42 (m, 1H), 7.21 (d, J=8.3 Hz, 2H), 5.64 (s, 2H),2.69 (d, J=8.0 Hz, 2H), 1.81-1.67 (m, 2H), 1.47-1.35 (m, 2H), 0.93 (t,J=7.3 Hz, 3H).

Intermediate 384b:2-butyl-4-chloro-1-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

4′-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-chloro-[1,1′-biphenyl]-2-carbonitrile(384a, 4.37 g, 10.6 mmol) was dissolved in H₂O (20 mL)/1-butanol (20mL). The reaction mixture was cooled to 0° C. 2M 2-methylbut-2-ene inTHF (15.90 mL, 31.8 mmol) was added to the reaction mixture followed bysodium dihydrogen phosphate (2.54 g, 21.20 mmol) and then sodiumchlorite (1.917 g, 21.20 mmol) at 0 C. The reaction mixture was allowedto warm to RT and stir at RT for 4 days. The reaction mixture was thenquenched with 10% aq. sodium sulfite (53.4 g, 42.4 mmol) at 0° C. andthen was allowed to stir for 30 min at RT. The reaction mixture was thendiluted with EtOAc and H₂O. The aq. phase was washed (3×) with EtOAc.The combined organic phases were washed with brine, dried with sodiumsulfate, filtered and concentrated to yield the title compound2-butyl-4-chloro-1-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (384b). The product was brought forward without furtherpurification. LC-MS (Method A2): 0.96 min, [M+H]⁺=428.0.

Intermediate 384c:2-butyl-4-chloro-1-((5′-chloro-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

To a pressure-rate 40 mL vial containing2-butyl-4-chloro-1-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (384b, 0.600 g, 1.401 mmol) was added dibutyltin oxide (0.349 g,1.401 mmol) and toluene (20.01 ml) followed by TMS-N₃ (0.930 ml, 7.00mmol). The reaction mixture was sealed and heated at 100° C. behind ablast shield overnight. The reaction mixture was diluted with hexanesand the solid was filtered off to yield the title compound (384c). Theproduct was brought forward without further purification. LC-MS: MS(ESI) 471.0 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.58 (d, J=8.2 Hz, 1H),7.42 (dd, J=8.2, 2.1 Hz, 1H), 7.36-7.24 (m, 1H), 7.07 (br d, J=8.2 Hz,2H), 6.88 (br d, J=7.9 Hz, 2H), 5.66 (br s, 2H), 2.89 (br d, J=7.3 Hz,2H), 1.56-1.39 (m, J=7.5, 7.5 Hz, 2H), 1.32-1.19 (m, 2H), 0.80 (t, J=7.5Hz, 3H).

Intermediate 384d:2-butyl-4-chloro-1-((5′-chloro-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

2-butyl-4-chloro-1-((5′-chloro-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (384c, 2.46 g, 5.22 mmol) was dissolved in THF (52.2 ml). TEA(2.182 ml, 15.66 mmol) was added followed by trityl-Cl (2.182 g, 7.83mmol). The reaction mixture was allowed to stir at RT for 2 h. 1M LiOH(15.66 ml, 15.66 mmol) was then added and the reaction mixture wasallowed to stir for 20 min at RT. The reaction mixture was thenconcentrated onto celite and purified by ISCO (0-20% MeOH/DCM) to affordthe title compound (384d, 1.88 g, 2.63 mmol, 50.5% yield). LC-MS: MS(ESI) m/z: 713.3 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.98-7.84 (m, 1H),7.56-7.31 (m, 10H), 7.12-7.07 (m, 3H), 6.93 (d, J=8.0 Hz, 6H), 6.80 (d,J=8.3 Hz, 2H), 5.46 (s, 2H), 2.55 (t, J=7.7 Hz, 2H), 1.78-1.67 (m, 2H),1.36-1.23 (m, 2H), 0.96-0.81 (m, 3H).

Intermediate 384e: lithium2-butyl-4-chloro-1-((5′-chloro-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylate

2-butyl-4-chloro-1-((5′-chloro-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (384d, 1.88 g, 2.63 mmol) was dissolved in THF (15 mL). 1M LiOH(2.90 mL, 2.90 mmol) was added and the reaction mixture was allowed tostir at RT for 1 h. The reaction mixture was then concentrated andazeotroped with toluene (3×) to afford the title compound (384e). Theproduct was brought forward without further purification. LC-MS (MethodA2): 1.20 min, [H]⁺=713.2.

Example 384:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid

To a pressure-rated vial containing lithium2-butyl-4-chloro-1-((5′-chloro-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylate(384e, 71 mg, 0.099 mmol), 2nd generation xphos precatalyst (15.53 mg,0.020 mmol) and phenylboronic acid (48 mg, 0.40 mmol) was added dioxane(1000 μl) followed by 2 M K₃PO₄ (2 M aq) (99 μl, 0.197 mmol). Thereaction mixture was sparged with N₂ for 2 min before being sealed andheated at 65° C. for 2 h. The reaction mixture was diluted with EtOAcand filtered through celite. The filtrate was concentrated and the cruderesidue was dissolved in DCM (4 mL). TFA (7.60 μl, 0.099 mmol) was addedfollowed by triethylsilane (15.76 μl, 0.099 mmol). The reaction mixturewas allowed to stir at RT for 30 min. The reaction mixture was thenconcentrated, dissolved in DMF, filtered and purified via preparativeLC-MS (Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A:5:95 ACN: H₂O with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 ACN:H₂O with 0.1% trifluoroacetic acid; Gradient: 30-70% B over 20 min, thena 5-minute hold at 100% B; Flow: 20 mL/min) to afford the title compound(Example 384, 14.5 mg, 0.028 mmol, 28.6% yield).). LC-MS (Method A4):1.989 min, [M+H]⁺=513.2; ¹H NMR (500 MHz, DMSO-d₆) δ 7.86 (d, J=7.9 Hz,1H), 7.81 (d, J=7.6 Hz, 2H), 7.75 (d, J=5.8 Hz, 2H), 7.55-7.48 (m, 2H),7.44 (d, J=7.3 Hz, 1H), 7.19 (d, J=7.9 Hz, 2H), 6.99 (d, J=7.9 Hz, 2H),5.61 (s, 2H), 2.59 (t, J=7.6 Hz, 2H), 1.53 (t, J=7.3 Hz, 2H), 1.36-1.19(m, 2H), 0.82 (t, J=7.2 Hz, 3H).

The following examples have been similarly prepared from Intermediate384e and the appropriate boronic acid or pinacol boronate as describedabove for Example 384.

LC-MS m/z [M + H]⁺; RT ¹H NMR (500 MHz, DMSO-d₆) Ex Structure MW (MethodA4) δ ppm 385

543.18 544.1; 1.285 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.33(br d, J = 2.4 Hz, 1H), 7.93 (br d, J = 7.9 Hz, 1H), 7.84 (s, 1H),7.81-7.73 (m, 2H), 7.27-7.11 (m, J = 7.9 Hz, 2H), 7.04-6.94 (m, J = 7.9Hz, 2H), 5.60 (s, 2H), 3.92 (s, 3H), 2.69- 2.57 (m, 2H), 1.59-1.44 (m,2H), 1.33-1.15 (m, 2H), 0.81 (br t, J = 7.2 Hz, 3H). 386

542.19 543.5; 1.562 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.94(s, 1H), 7.66 (br d, J = 8.2 Hz, 1H), 7.61-7.51 (m, 2H), 7.10 (br d, J =8.2 Hz, 2H), 6.91 (br d, J = 7.9 Hz, 2H), 5.58 (br s, 2H), 3.88-3.67 (m,3H), 1.55-1.45 (m, 2H), 1.35- 1.14 (m, 2H), 1.09-1.02 (m, 2H), 1.02-0.94(m, 2H), 0.80 (t, J = 7.3 Hz, 3H). 387

552.61 553.4; 1.592 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.33(s, 1H), 7.78- 7.69 (m, 2H), 7.68-7.63 (m, 1H), 7.59 (d, J = 7.9 Hz,1H), 7.11 (br d, J = 7.9 Hz, 2H), 6.90 (br d, J = 7.9 Hz, 2H), 5.59 (brs, 2H), 2.59-2.54 (m, 2H), 1.60-1.42 (m, 2H), 1.30-1.20 (m, 2H), 0.80(t, J = 7.3 Hz, 3H). 388

612.198 613.2; 2.089 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (br s, 1H),7.72 (d, J = 7.9 Hz, 1H), 7.60 (br d, J = 8.2 Hz, 1H), 7.55 (s, 1H),7.11 (br d, J = 7.9 Hz, 2H), 6.97 (br d, J = 8.0 Hz, 2H), 5.59 (s, 2H),4.71-4.53 (m, 1H), 2.60-2.56 (m, 2H), 1.53-1.44 (m, J = 6.6 Hz, 8H),1.32-1.14 (m, 2H), 0.79 (br t, J = 7.3 Hz, 3H). 389

516.179 517.3; 1.430 min ¹H NMR (500 MHz, DMSO-d₆) δ 8.26 (s, 1H), 7.97(s, 1H), 7.66 (br d, J = 8.2 Hz, 1H), 7.62-7.55 (m, 2H), 7.18-7.07 (m, J= 7.9 Hz, 2H), 6.99-6.87 (m, J = 7.9 Hz, 2H), 5.60 (br s, 2H), 3.90-3.85 (m, 3H), 2.61-2.53 (m, 2H), 1.58-1.49 (m, 2H), 1.32-1.14 (m, 2H),0.83 (br t, J = 7.2 Hz, 3H). 390

583.210 584.1; 1.574 min . ¹H NMR (500 MHz, DMSO-d₆) δ 7.81 (d, J = 8.2Hz, 2H), 7.75- 7.70 (m, 1H), 7.70-7.66 (m, 1H), 7.59 (s, 1H), 7.49 (d, J= 8.1 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 8.0 Hz, 2H), 5.63(br. s., 2H), 3.00 (br. s., 3H), 2.96 (br. s., 3H), 2.53-2.52 (m, 2H),1.56- 1.41 (m, 2H), 1.30-1.19 (m, 2H), 0.80 (t, J = 7.3 Hz, 3H). 391

551.184 552.3; 1.7899 min ¹H NMR (500 MHz, DMSO-d₆) δ 11.36 (br s, 1H),7.91 (d, J = 7.8 Hz, 1H), 7.85-7.76 (m, 2H), 7.73-7.63 (m, 2H), 7.48 (d,J = 8.1 Hz, 1H), 7.26-7.10 (m, 4H), 6.97 (d, J = 8.1 Hz, 2H), 5.62 (s,2H), 2.60-2.56 (m, 2H), 1.53 (br t, J = 7.4 Hz, 2H), 1.33-1.15 (m, 2H),0.82 (t, J = 7.3 Hz, 3H).

Example 392:1-((5′-(1H-indol-4-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid

Example 392 was prepared in similar manner as Example 384, however, only10 equiv. of TFA was used and MeOH was used as the solvent in place ofDCM. LC-MS (Method A4): 1.757 min, [M+H]⁺=552.1; ¹H NMR (500 MHz,DMSO-d₆) δ 11.36 (br s, 1H), 7.88 (br d, J=7.9 Hz, 1H), 7.82-7.73 (m,2H), 7.54-7.41 (m, 2H), 7.28-7.15 (m, 4H), 7.09-6.93 (m, 2H), 6.64 (brs, 1H), 5.61 (s, 2H), 3.18 (s, 1H), 2.59 (s, 2H), 1.54-1.44 (m, 2H),1.34-1.14 (m, J=7.3 Hz, 2H), 0.80 (t, J=7.3 Hz, 3H).

Example 393:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxamide

1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid, TFA salt (Example 384, 16 mg, 0.026 mmol) was dissolved in THF (2mL). CDI (62.1 mg, 0.383 mmol) was added and the reaction mixture wasallowed to stir at RT for 1 h. Ammonium hydroxide (0.142 mL, 1.276 mmol)was then added and the reaction was allowed to stir at RT for 1 h. Thereaction mixture was concentrated, taken up in DMF, filtered andpurified via preparative LC-MS (Column: Waters XBridge C18, 2.1 mm×50mm, 1.7 μm particles; Mobile Phase A: 5:95 ACN:H₂O with 10 mM NH₄OAc;Mobile Phase B: 95:5 ACN:H₂O with 10 mM NH₄OAc; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min) to afford the title compound (Example 393, 10.3 mg,0.020 mmol, 79% yield). LC-MS (Method A4): 1.956 min, [M+H]⁺=512.0; ¹HNMR (500 MHz, DMSO-d₆) δ 7.89-7.69 (m, 5H), 7.54-7.47 (m, 2H), 7.46-7.39(m, 1H), 7.18 (d, J=7.7 Hz, 2H), 7.01 (d, J=7.7 Hz, 2H), 5.54 (s, 2H),2.57-2.52 (m, 2H), 1.55-1.40 (m, 2H), 1.34-1.18 (m, 2H), 0.81 (t, J=7.2Hz, 3H).

Example 394:2-butyl-4-chloro-1-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxamide

Example 394 was synthesized from Example 404 using the procedure used tosynthesize Example 393 to give the title compound (Example 394, 2.3 mg,4.36 μmol, 4.13% yield). MS (ESI) (M+H)⁺=528.0. ¹H NMR (500 MHz,DMSO-d₆) δ 7.83-7.76 (m, 3H), 7.74-7.65 (m, 3H), 7.54-7.47 (m, 2H),7.46-7.34 (m, 4H), 7.12 (d, J=7.9 Hz, 2H), 5.58 (s, 2H), 2.61-2.56 (m,2H), 1.50 (t, J=7.3 Hz, 2H), 1.31-1.18 (m, 2H), 0.81 (t, J=7.3 Hz, 3H).LC-MS retention time (Method A4): 2.113 min

Example 395: ethyl1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate

Intermediate 395a: methyl4-ethyl-2-propyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carboxylate

2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (272mg, 0.917 mmol), methyl 4-ethyl-2-propyl-1H-imidazole-5-carboxylate (150mg, 0.764 mmol) were dissolved in DMF (10 mL) at 0° C. 60% sodiumhydride in mineral oil (33.6 mg, 0.841 mmol) was added to the reactionmixture which was allowed to stir at RT for 15 h. The reaction mixturewas cooled to 0° C. and quenched with saturated ammonium chloride. Theaq. layer was extracted (3×) with EtOAc. The combined organic layer waswashed with brine, dried with sodium sulfate, filtered and concentrated.The residue was purified by ISCO (0-100% EtOAc in hexane) to afford thetitle compound (395a, 100 mg, 0.243 mmol, 31.7% yield). LC-MS (MethodA2): 0.85 min, [M+H]⁺=413.1; ¹H NMR (500 MHz, CDCl₃) δ 7.75 (d, J=8.0Hz, 2H), 6.95 (d, J=7.7 Hz, 2H), 5.54 (s, 2H), 3.76 (s, 3H), 2.91 (q,J=7.5 Hz, 2H), 2.65-2.53 (m, 2H), 1.77-1.62 (m, 2H), 1.26 (t, J=7.4 Hz,3H), 0.94 (t, J=7.4 Hz, 3H).

Intermediate 395b: methyl1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate

To a solution of methyl4-ethyl-2-propyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carboxylate(395a, 100 mg, 0.243 mmol) and 3-bromo-[1,1′-biphenyl]-4-carbonitrile(032a, 120 mg, 0.315 mmol) in dioxane (3 mL) was added K₃PO₄ (2 M, aq)(0.364 mL, 0.728 mmol) followed by PdCl₂(dppf) (17.75 mg, 0.024 mmol).The resulting mixture was sparged with N₂ for 2 min before being sealedand heated at 120° C. for 45 min in the microwave. The reaction mixturewas diluted with EtOAc and filtered through celite. The filtrate wasconcentrated and the residue was purified by ISCO (0-100% EtOAc inhexane) to afford the title compound (395b, 70 mg, 0.151 mmol, 62.3%yield). LC-MS (Method A2): 0.91 min, [M+H]⁺=464.1; ¹H NMR (500 MHz,CDCl₃) δ 7.88-7.81 (m, 1H), 7.72-7.71 (m, 1H), 7.69-7.66 (m, 1H),7.66-7.63 (m, 2H), 7.60-7.56 (m, 2H), 7.53-7.47 (m, 2H), 7.48-7.44 (m,1H), 7.18-7.09 (m, 2H), 3.82 (s, 3H), 3.04-2.86 (m, 2H), 2.77-2.60 (m,2H), 1.82-1.70 (m, 2H), 1.34-1.20 (m, 3H), 1.05-0.95 (m, 3H).

Example 395: ethyl1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate

Example 395 was synthesized from 395b using the procedure described forExample 345. The crude residue was purified by reverse phase HPLC(Xbridge Prep Shield RP18, 15 min gradient of 20-100% B. A=H₂O/MeOH 10mM NH₄OAc 90:10. B=H₂O/MeOH 10 mM NH₄OAc 10:90) to afford the titlecompound (Example 395, 4.5 mg, 0.0086 mmol, 29.8%). LC-MS (Method A4):1.788 min, [M+H]⁺=521.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.86-7.74 (m, 3H),7.71-7.63 (m, 2H), 7.54-7.45 (m, 2H), 7.41 (d, J=7.3 Hz, 1H), 7.14 (d,J=8.2 Hz, 2H), 6.88 (d, J=7.9 Hz, 2H), 5.50 (s, 2H), 4.15 (q, J=7.0 Hz,2H), 2.77 (q, J=7.3 Hz, 2H), 2.58-2.55 (m, 2H), 1.62-1.44 (m, 2H),1.24-1.09 (m, 6H), 0.84 (t, J=7.3 Hz, 3H).

Example 396:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylicacid

Ethyl1-46′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate(Example 395, 130 mg, 0.250 mmol) was dissolved in 1M NaOH (1.248 mL,1.248 mmol)/MeOH (1.2 mL). The reaction mixture was sealed and stirredat 100° C. for 2 h. The reaction mixture was then acidified with 10%citric acid and extracted (3×) with EtOAc. The combined organic layerwas washed with brine dried with sodium sulfate, filtered andconcentrated. The residue was redissolved in MeOH, filtered and purifiedby reverse phase HPLC (Xbridge Prep Shield RP18, 15 min gradient of20-100% B. A=H₂O/MeOH 10 mM NH₄OAc 90:10. B═H₂O/MeOH 10 mM NH₄OAc 10:90)to afford the title compound (Example 396, 65 mg, 0.132 mmol, 52.8%yield). LC-MS (Method A4): 1.630 min, [M+H]⁺=493.1; ¹H NMR (500 MHz,DMSO-d₆) δ 7.86-7.61 (m, 5H), 7.53-7.36 (m, 3H), 7.17 (d, J=7.6 Hz, 2H),6.89 (d, J=7.6 Hz, 2H), 5.55 (br. s., 2H), 2.80 (q, J=7.3 Hz, 2H),2.50-2.47 (m, 2H), 1.66-1.52 (m, 2H), 1.15 (t, J=7.3 Hz, 3H), 0.88 (t,J=7.3 Hz, 3H).

Example 397:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-N-(2,2,2-trifluoroethyl)-1H-imidazole-5-carboxamide

Example 397 was synthesized from Example 396 and trifluoroethyl amineusing the same procedure described for the synthesis of Example 393.LC-MS (Method A4): 1.776 min, [M+H]⁺=573.9; ¹H NMR (500 MHz, DMSO-d₆) δ8.60 (t, J=6.1 Hz, 1H), 7.82-7.59 (m, 5H), 7.55-7.45 (m, 2H), 7.45-7.35(m, 1H), 7.11 (d, J=7.3 Hz, 2H), 6.94 (d, J=7.6 Hz, 2H), 5.31 (s, 2H),4.11-3.86 (m, 2H), 3.72-3.64 (m, 2H), 2.64 (q, J=7.5 Hz, 2H), 1.60-1.42(m, 2H), 1.11 (t, J=7.5 Hz, 3H), 0.84 (t, J=7.2 Hz, 3H).

Example 398:1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxamide

Example 398 was synthesized from Example 396 using the same proceduredescribed for the synthesis of Example 393. LC-MS (Method A4): 1.479min, [M+H]⁺=492.4; ¹H NMR (500 MHz, DMSO-d₆) δ 7.78 (d, J=7.3 Hz, 4H),7.64 (s, 1H), 7.57-7.43 (m, 2H), 7.44-7.36 (m, 1H), 7.32 (br. s., 2H),7.14 (br. s., 2H), 6.95 (d, J=6.4 Hz, 2H), 5.40 (s, 2H), 2.67 (q, J=7.5Hz, 2H), 2.49-2.44 (m, 2H), 1.63-1.46 (m, 2H), 1.14 (t, J=7.3 Hz, 3H),0.86 (t, J=7.3 Hz, 3H).

Example 399:4-ethyl-1-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-1H-imidazole-5-carboxylicacid

Methyl1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate(395b, 56 mg, 0.121 mmol) was dissolved in DMSO (2 mL). Hydroxylaminehydrochloride (58.8 mg, 0.846 mmol) was added followed by NaHCO₃ (71.0mg, 0.846 mmol) in a pressure-rated vial. The reaction mixture wasallowed to stir at 80° C. for 15 hours. The reaction mixture was dilutedwith H₂O and filtered. The precipitate was then dissolved in THF (5 mL).DBU (0.091 mL, 0.604 mmol) was added followed by CDI (98 mg, 0.604mmol). The reaction was allowed to stir at RT for 15 min. The reactionmixture was concentrated. The resulting residue was dissolved in MeOH (1mL). 1M NaOH (0.906 mL, 1.812 mmol) was added and the reaction wasallowed to stir at 50° C. for 15 hours. The reaction was acidified withAcOH (0.138 mL, 2.416 mmol) and diluted with EtOAc and H₂O. The aq.phase was washed with EtOAc 3×. The combined organic phase was driedwith sodium sulfate, filtered and concentrated. The residue wasdissolved in DMF, filtered and purified via preparative LC-MS (Column:Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95ACN:H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN:H₂O with 10 mMNH₄OAc; Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a0.75 min hold at 100% B; Flow: 1 mL/min) to afford the title compound(Example 399, 13.3 mg, 0.025 mmol, 20.35% yield). LC-MS (Method A4):1.581 min, [M+H]⁺=509.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.92-7.70 (m, 5H),7.57-7.35 (m, 5H), 7.19-7.07 (m, 2H), 5.74 (br. s., 2H), 2.96-2.87 (m,2H), 2.78 (t, J=7.3 Hz, 2H), 1.64-1.49 (m, 2H), 1.21 (t, J=7.3 Hz, 3H),0.86 (t, J=7.3 Hz, 3H).

Example 400:1-((6′-carboxy-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylicacid

Intermediate 400a: methyl4″-(hydroxymethyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylate

To a vial containing 4-(hydroxymethyl)phenylboronic acid (251 mg, 1.650mmol), methyl 3-chloro-[1,1′-biphenyl]-4-carboxylate (370 mg, 1.500mmol) and 2nd generation xphos precatalyst (59.0 mg, 0.075 mmol) wasadded dioxane (7499 μl) followed by 2 M K₃PO₄ (2 M aq) (1500 μl, 3.00mmol). The reaction mixture was sparged with N₂ for 2 min before beingsealed and heated at 85° C. After 2.5 h of heating the reaction mixturewas concentrated onto celite and purified by ISCO (0-100% EtOAc) toafford the title compound (400a, 470 mg, 1.476 mmol, 82% yield). LC-MS(Method A2): 1.00 min, [M+H]⁺=319.1.1; ¹H NMR (400 MHz, CDCl₃) δ 7.94(d, J=8.1 Hz, 1H), 7.66-7.61 (m, 3H), 7.58 (d, J=1.8 Hz, 1H), 7.51-7.34(m, 7H), 4.77 (br. s., 2H), 3.69 (s, 3H).

Intermediate 400b: methyl4″-(bromomethyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylate

To a flask containing methyl4″-(hydroxymethyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylate (400a, 470 mg,1.476 mmol) was added DCM (14.800 mL) followed by triphenylphosphine(774 mg, 2.95 mmol). Carbon tetrabromide (979 mg, 2.95 mmol) was thenadded at RT and the reaction mixture was allowed to stir at RT for 1 h.The crude reaction mixture was concentrated directly onto celite andpurified by ISCO (0-70% EtOAc/Hex) to afford the title compound (400b,280 mg, 0.734 mmol, 49.7% yield).). ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d,J=8.1 Hz, 1H), 7.64 (ddd, J=8.1, 5.6, 1.5 Hz, 3H), 7.58 (d, J=1.8 Hz,1H), 7.50-7.36 (m, 5H), 7.36-7.31 (m, 2H), 4.56 (s, 2H), 3.68 (s, 3H).

Intermediate 400c: ethyl4-ethyl-1-((6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-1H-imidazole-5-carboxylate

Ethyl 4-ethyl-2-propyl-1H-imidazole-5-carboxylate, HCl (78 mg, 0.315mmol) was dissolved in DMF (5 mL) along with methyl4″-(bromomethyl)-[1,1′:3′,1″-terphenyl]-4′-carboxylate (400b, 80 mg,0.210 mmol) at 0° C. 60% sodium hydride (30.2 mg, 1.259 mmol) was addedand the reaction was allowed to stir at 0° C. for 10 min then at RT for30 min. The reaction mixture was quenched with saturated ammoniumchloride then diluted with EtOAc, washed with 10% LiCl 3×, brine, driedwith sodium sulfate, filtered and concentrated. The residue was purifiedby ISCO (0-100% EtOAc in hexane) to afford the title compound (400c, 18mg, 0.035 mmol, 16.80% yield).). LC-MS (Method A2): 1.00 min,[M+H]⁺=511.15. ¹H NMR (500 MHz, CDCl₃) δ 7.99-7.92 (m, 1H), 7.67-7.63(m, 3H), 7.59-7.55 (m, 1H), 7.51-7.45 (m, 3H), 7.44-7.41 (m, 1H),7.36-7.31 (m, 2H), 7.07-7.01 (m, 1H), 5.62-5.57 (m, 2H), 4.32-4.22 (m,2H), 3.66 (s, 3H), 2.99-2.88 (m, 2H), 2.71-2.62 (m, 2H), 1.81-1.68 (m,2H), 1.37-1.31 (m, 3H), 1.04-0.86 (m, 3H).

Example 400:1-((6′-carboxy-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylicacid

Ethyl4-ethyl-1-((6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-1H-imidazole-5-carboxylate(400c, 18 mg, 0.035 mmol) was dissolved in MeOH (1 mL). 1M NaOH (0.529mL, 0.529 mmol) was added and the reaction was allowed to stir at 65° C.in a sealed pressure rated vial for 18 h. The reaction mixture wasconcentrated, dissolved in DMF, filtered and purified via preparativeLC-MS (XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN:H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc;Gradient: 13-53% B over 20 min, then a 6-minute hold at 100% B; Flow: 20mL/min) to afford the title compound (Example 400, 13.8 mg, 0.029 mmol,81% yield).). LC-MS (Method A4): 1.542 min, [M+H]⁺=469.2; ¹H NMR (500MHz, DMSO-d₆) δ 7.84-7.67 (m, 4H), 7.56 (s, 1H), 7.48 (t, J=7.5 Hz, 2H),7.43-7.32 (m, 3H), 7.02 (d, J=7.6 Hz, 2H), 5.61 (s, 2H), 2.81 (q, J=7.3Hz, 2H), 2.59-2.56 (m, 2H), 1.67-1.47 (m, 2H), 1.15 (t, J=7.5 Hz, 3H),0.87 (t, J=7.2 Hz, 3H).

Example 401: ethyl1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate

Intermediate 401a: ethyl4-(2-hydroxypropan-2-yl)-2-propyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carboxylate

To a solution of ethyl4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (300 mg,1.248 mmol) and 4-(bromomethyl)benzeneboronic acid pinacol ester (371mg, 1.248 mmol) in Acetone (4994 μl) was added K₂CO₃ (345 mg, 2.497mmol). The reaction mixture was sealed and heated at 60° C. overnight.The reaction mixture was then diluted with EtOAc, filtered over celite,and then concentrated onto celite for purification by ISCO (0-100%EtOAc/Hexanes) to afford the title compound (401a, 370 mg, 0.811 mmol,64.9% yield). LC-MS (Method A2): 0.89 min, [M+H]⁺=457.1; ¹H NMR (400MHz, CDCl₃) δ 7.74 (d, J=8.1 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 5.45 (s,2H), 4.18 (q, J=7.3 Hz, 2H), 2.64-2.56 (m, 2H), 1.75-1.65 (m, 2H),1.37-1.30 (m, 12H), 1.13 (t, J=7.0 Hz, 3H), 0.93 (t, J=7.4 Hz, 3H).

Intermediate 401b: ethyl1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate

To a solution of ethyl4-(2-hydroxypropan-2-yl)-2-propyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carboxylate(401a, 265 mg, 0.581 mmol) and 3-bromo-[1,1′-biphenyl]-4-carbonitrile(032a, 180 mg, 0.697 mmol) in dioxane (5811 μl) was added K₃PO₄ (2 M,aq) (581 μl, 1.162 mmol) followed by PdCl₂(dppf) (42.5 mg, 0.058 mmol).The resulting mixture was sparged with N₂ for 2 min before being sealedand heated at 120° C. for 45 min in the microwave. The reaction mixturewas diluted with EtOAc and the organic phase was filtered over a mixtureof Celite/MgSO₄. The resulting filtrate was concentrated onto celite andpurified by ISCO (0-100% EtOAc/Hexanes) to afford the title compound(401b, 265 mg, 0.522 mmol, 90% yield). LC-MS (Method A2): 0.96 min,[M+H]⁺=508.1. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J=8.4 Hz, 1H),7.70-7.60 (m, 4H), 7.60-7.55 (m, 2H), 7.52-7.40 (m, 3H), 7.06 (d, J=8.4Hz, 2H), 5.79 (br. s., 1H), 5.53 (s, 2H), 4.24 (q, J=7.3 Hz, 2H),2.71-2.64 (m, 2H), 1.82-1.69 (m, 2H), 1.24 (s, 6H), 1.17 (t, J=7.2 Hz,3H).

Example 401: ethyl1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate

Example 401 was synthesized from 401b using the procedure described forexample 345. The crude residue was purified by reverse phase HPLC(Xbridge Prep Shield RP18, 15 min gradient of 20-100% B. A=H₂O/MeOH 10mM NH₄OAc 90:10. B=H₂O/MeOH 10 mM NH₄OAc 10:90) to afford the titlecompound (Example 401, 3.9 mg, 6.66 μmol, 7.33% yield). LC-MS (MethodA4): 1.774 min, [M+H]⁺=551.1; ¹H NMR (500 MHz, DMSO-d₆) δ 7.91-7.69 (m,5H), 7.56-7.39 (m, 3H), 7.18 (d, J=7.9 Hz, 2H), 6.94 (d, J=7.9 Hz, 2H),5.48 (s, 2H), 4.16 (q, J=7.2 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 1.61-1.52(m, 2H), 1.50 (s, 6H), 1.08 (t, J=7.0 Hz, 3H), 0.88 (t, J=7.3 Hz, 3H).

Example 402: sodium1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate

To a solution of ethyl1-46′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate(Example 401, 4 mg, 6.97 μmol) in THF (1 mL) was added NaOH (1 M aq)(8.37 μl, 8.37 μmol). The reaction mixture was stirred at RT for 16 h.The reaction mixture was then sealed and heated at 65° C. After 1.5 h ofstirring more NaOH (1 M aq) (8.37 μl, 8.37 μmol) was added, and heatingwas continued for another 1.5 h. The reaction mixture was concentratedto afford the title compound without further purification. LC-MS (MethodA2): 0.77 min, [M+H]⁺=523.1; ¹H NMR (400 MHz, MeOH-d₄) δ 7.62-7.46 (m,5H), 7.39-7.33 (m, 2H), 7.29-7.22 (m, 1H), 7.03 (d, J=8.1 Hz, 2H), 6.82(d, J=8.4 Hz, 2H), 5.66 (s, 2H), 2.51-2.44 (m, 2H), 1.80-1.76 (m, 2H),1.46 (s, 6H), 0.80 (t, J=7.4 Hz, 3H).

Example 403:4-(2-hydroxypropan-2-yl)-1-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-1H-imidazole-5-carboxylicacid, Na+

Intermediate 403a: ethyl4-(2-hydroxypropan-2-yl)-1-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-1H-imidazole-5-carboxylate

Ethyl1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate(401b, 50 mg, 0.098 mmol) was dissolved in 1-butyl-3-methylimidazoliumacetate (985 μl) along with hydroxylamine hydrochloride (171 mg, 2.462mmol). The reaction mixture was allowed to stir at 50° C. for 48 h. Thereaction was diluted with H₂O and the amidoxime intermediate wasfiltered off and washed with H₂O. The amidoxime intermediate wasdissolved in THF (2 mL). DBU (0.071 mL, 0.472 mmol) was added followedby CDI (76 mg, 0.472 mmol). The reaction mixture was allowed to stir atRT for 20 min. The reaction mixture was concentrated and the cruderesidue was dissolved in DMF, filtered and purified via preparativeLC-MS (XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN:H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc;Gradient: 13-53% B over 20 min, then a 6-minute hold at 100% B; Flow: 20mL/min) to afford the title compound (403a, 24 mg, 0.042 mmol, 44.9%yield). LC-MS (Method A2): 1.806 min, [M+H]⁺=567.4. ¹H NMR (500 MHz,DMSO-d₆) δ 7.83 (d, J=7.9 Hz, 1H), 7.79 (d, J=7.6 Hz, 2H), 7.75-7.68 (m,2H), 7.54-7.29 (m, 5H), 7.01 (d, J=7.9 Hz, 2H), 5.51 (s, 2H), 4.16 (q,J=7.1 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H), 1.67-1.55 (m, 2H), 1.09 (t, J=7.0Hz, 3H), 0.90 (t, J=7.3 Hz, 3H).

Example 403:4-(2-hydroxypropan-2-yl)-1-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-1H-imidazole-5-carboxylicacid, Na+

Ethyl4-(2-hydroxypropan-2-yl)-1-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-propyl-1H-imidazole-5-carboxylate(403a, 20 mg, 0.035 mmol) was dissolved in MeOH (1 mL). 1M NaOH (0.071mL, 0.071 mmol) was added to the reaction mixture and the reactionmixture was allowed to stir at 65° C. for 30 h. Additional 1M NaOH(0.071 mL, 0.071 mmol) was added to the reaction mixture which wasallowed to stir at 65° C. for an additional 6 hours. The reactionmixture was concentrated to dryness, redissolved in MeOH and filtered.The filtrate was concentrated to afford the title compound withoutfurther purification (Example 403, 20 mg, 0.034 mmol, 96% yield).).LC-MS (Method A2): 0.83 min, [M+H]⁺=539.1. ¹H NMR (500 MHz, MeOH-d4) δ7.71-7.57 (m, 5H), 7.50-7.44 (m, 2H), 7.41-7.34 (m, 3H), 7.10-6.99 (m,2H), 5.91-5.71 (m, 2H), 2.69-2.51 (m, 2H), 1.59 (s, 6H), 1.59-1.53 (m,2H), 0.94 (t, J=7.3 Hz, 3H).

Example 404:2-butyl-4-chloro-1-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 404a:4″-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

To a solution of2-butyl-4-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carbaldehyde(035a, 523 mg, 1.299 mmol) and 3-bromo-[1,1′-biphenyl]-4-carbonitrile(032a, 335 mg, 1.299 mmol) in 4:1 toluene/EtOH (10 mL) was added K₃PO₄(2 M, aq) (1.948 mL, 3.90 mmol) followed by PdCl₂(dppf) (95 mg, 0.130mmol). The resulting mixture was sparged with N₂ for 2 min before beingsealed and heated at 120° C. for 45 min in the microwave. The reactionmixture was then filtered through celite and the filtrate wasconcentrated and the residue was purified by ISCO (0-100% EtOAc/Hexanes)to afford the title compound (404a, 190 mg, 0.419 mmol, 32.2% yield).LC-MS: MS (ESI) m/z: 454.0 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.87-7.82(m, 1H), 7.73-7.67 (m, 2H), 7.66-7.58 (m, 4H), 7.57-7.40 (m, 3H),7.25-7.18 (m, 2H), 5.65 (s, 2H), 2.75-2.64 (m, 2H), 1.83-1.69 (m, 2H),1.47-1.35 (m, 2H), 0.94 (s, 3H).

Intermediate 404b:2-butyl-4-chloro-1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

404b was synthesized using the procedure described for 345c. LC-MS: MS(ESI) m/z: 470.05 (M+H)+. ¹H NMR (500 MHz, DMSO-d₆) δ 8.02 (d, J=7.9 Hz,1H), 7.89-7.79 (m, 4H), 7.72-7.63 (m, J=7.9 Hz, 2H), 7.55-7.45 (m, 3H),7.24-7.14 (m, J=7.9 Hz, 2H), 5.70 (s, 2H), 2.65 (t, J=7.5 Hz, 2H), 1.55(br t, J=7.5 Hz, 2H), 1.33-1.22 (m, 2H), 0.81 (t, J=7.3 Hz, 3H).

Example 404:2-butyl-4-chloro-1-((6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Hydroxylamine hydrochloride (53.2 mg, 0.766 mmol) was dissolved inethanol (638 μl). Potassium tert-butoxide (71.6 mg, 0.638 mmol) wasadded and the reaction mixture was allowed to vigorously stir for 2 h atRT.2-butyl-4-chloro-1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (404b, 30 mg, 0.064 mmol) was then added to the reaction mixturewhich was sealed and allowed to stir at 80° C. for 18 h. The reactionmixture was diluted with H₂O and the amidoxime intermediate was filteredoff and dissolved in THF (3 mL). DBU (0.036 mL, 0.239 mmol) was addedfollowed by CDI (90 mg, 0.557 mmol). The reaction mixture was allowed tostir at RT for 15 min. The reaction mixture was concentrated, dissolvedin DMF, filtered and purified via preparative LC-MS (XBridge C18, 19×200mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 10 mM NH₄OAc;Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc; Gradient: 13-53% B over20 min, then a 6-minute hold at 100% B; Flow: 20 mL/min) to afford thetitle compound (Example 404, 4.2 mg, 7.94 mol, 9.98% yield). LC-MS(Method A4): 2.102 min, [M+H]⁺=528.9. ¹H NMR (500 MHz, DMSO-d₆) δ7.86-7.63 (m, 5H), 7.53-7.47 (m, 2H), 7.43 (d, J=7.0 Hz, 1H), 7.38 (d,J=7.6 Hz, 2H), 7.08 (d, J=7.6 Hz, 2H), 5.67 (br. s., 2H), 2.61-2.56 (m,2H), 1.58-1.42 (m, 2H), 1.33-1.19 (m, 2H), 0.80 (t, J=7.3 Hz, 3H).

Example 405:2-butyl-4-chloro-1-((5′-(3,3-dimethylindolin-1-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 405a:2-butyl-4-chloro-1-((2′-cyano-5′-(3,3-dimethylindolin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid, TFA salt

To a vial containing2-butyl-4-chloro-1-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (384b, 00 mg, 0.364 mmol) was added 2nd generation ruphosprecatalyst (56.6 mg, 0.073 mmol) followed by sodium tert-butoxide (210mg, 2.185 mmol). THF (3 mL) was added followed by 3,3-dimethylindoline(161 mg, 1.093 mmol). The reaction mixture was degassed with N₂ and wasthen was sealed and heated at 65° C. for 18 h. The reaction mixture wasconcentrated onto celite and purified by reverse phase ISCO (15 mingradient of 0-100% B. A=H₂O/ACN/TFA 90:10:0.1. B=ACN/H₂O/TFA 90:10:0.1)to afford the title compound (405a, 70 mg, 0.107 mmol, 29.4% yield) asan orange solid. LC-MS (Method A2): 1.07 min, [M+H]⁺=539.10.

Example 405:2-butyl-4-chloro-1-((5′-(3,3-dimethylindolin-1-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 405 was synthesized from 405a according to the same procedureused for the synthesis of 403a to afford the title compound (Example405, 9.6 mg, 0.016 mmol, 24.72% yield). MS (ESI) m/z (M+H)⁺=598.15. ¹HNMR (500 MHz, DMSO-d₆) δ 7.94 (s, 1H), 7.57 (br d, J=8.5 Hz, 1H),7.40-7.30 (m, 3H), 7.27 (d, J=8.1 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H),7.17-7.02 (m, 4H), 6.97-6.79 (m, 1H), 5.66 (br s, 2H), 3.77 (s, 1H),3.17 (s, 1H), 2.89 (s, 2H), 2.73 (s, 2H), 2.59 (br s, 2H), 2.56-2.53 (m,3H), 1.50 (br s, 2H), 1.30 (s, 6H), 1.25 (br d, J=7.3 Hz, 2H), 1.16 (s,1H), 0.79 (br t, J=7.2 Hz, 3H). LC-MS retention time (Method A4): 2.318min

Example 406:2-butyl-4-chloro-1-((5′-(indolin-1-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 406 was synthesized from indoline and 384b according to the samesequence as described for Example 405. MS (ESI) m/z (M+H)⁺=570.1. ¹H NMR(500 MHz, DMSO-d₆) δ 7.57 (d, J=8.5 Hz, 1H), 7.39-7.29 (m, 3H), 7.23(dd, J=13.3, 7.5 Hz, 2H), 7.14-6.96 (m, 4H), 6.79 (t, J=7.3 Hz, 1H),5.71 (br. s., 2H), 4.01 (t, J=8.4 Hz, 2H), 3.11 (t, J=8.2 Hz, 2H),2.56-2.54 (m, 2H), 1.57-1.40 (m, 2H), 1.32-1.18 (m, 2H), 0.79 (t, J=7.3Hz, 3H). LC-MS retention time (Method A4): 2.132 min

Example 407:(S)-2-butyl-4-chloro-1-((5′-(3-methylpiperidin-1-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 407a:4′-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile

Intermediate 407a was synthesized according to the same procedure usedfor Intermediate 384a to afford the title compound (407a, 1.05 g, 2.65mmol, 71.2% yield). LC-MS: MS (ESI) m/z: 396.1 (M+H)⁺. ¹H NMR (500 MHz,CDCl₃) δ 9.80 (s, 1H), 7.80 (dd, J=8.5, 5.5 Hz, 1H), 7.55 (d, J=8.3 Hz,2H), 7.24-7.17 (m, 4H), 5.64 (s, 2H), 2.72-2.67 (m, 2H), 1.74 (t, J=7.7Hz, 2H), 1.46-1.33 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

Intermediate 407b:(S)-4′-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-(3-methylpiperidin-1-yl)-[1,1′-biphenyl]-2-carbonitrile

4′-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile(407a, 199 mg, 0.503 mmol) was dissolved in DMSO (1676 μl). Potassiumcarbonate (347 mg, 2.51 mmol) was added followed by(S)-3-methylpiperidine, HCl (150 mg, 1.106 mmol). The reaction mixturewas sealed and heated at 100° C. for 2 h. The reaction mixture wasdiluted with EtOAc and H₂O. The aq. phase was washed with EtOAc (3×) andthe combined organic phases were washed with brine, dried with sodiumsulfate, filtered and concentrated. The residue was purified by ISCO(0-100% EtOAc in hexane) to afford the title compound (407b, 194 mg,0.408 mmol, 81% yield). LC-MS (Method A2): 1.17 min, [M+H]⁺=475.1.

Intermediate 407c:(S)-2-butyl-4-chloro-1-((2′-cyano-5′-(3-methylpiperidin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 407c was synthesized from 407b according to the proceduredescribed for the synthesis of 345c to afford the title compound (407c,0.103 g, 0.211 mmol, 100%). LC-MS (Method A2): 1.07 min, [M+H]⁺=491.1.

Example 407:(S)-2-butyl-4-chloro-1-((5′-(3-methylpiperidin-1-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 407 was synthesized from 407c according to the proceduredescribed for Intermediate 403a to afford the title compound (Example407, 0.9 mg, 1.636 μmol, 2.60% yield). LC-MS (Method A4): 1.943 min,[M+H]⁺=550.1.

Example 408:1-((5′-(1H-indol-1-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid

Intermediate 408a:1-((5′-bromo-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid

408a was synthesized from 035a and 4-bromo-2-iodobenzonitrile accordingto the sequence described for the synthesis of 384b. LC-MS (Method A2):0.961 min, [M+H]⁺=473.95.

Intermediate 408b:2-butyl-4-chloro-1-((2′-cyano-5′-(1H-indol-1-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid, TFA salt

(S)-pyrrolidine-2-carboxylic acid (50.9 mg, 0.442 mmol),1-((5′-bromo-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid (408, 209 mg, 0.442 mmol), 1H-indole (311 mg, 2.65 mmol), copper(I)iodide (42.1 mg, 0.221 mmol) and potassium carbonate (305 mg, 2.210mmol) were added to a pressure-rated vial. DMSO (4421 μl) was added andthe reaction was evacuated and backfilled with Na (3×) then stirred at120° C. for 18 h. The reaction mixture was diluted with EtOAc andfiltered through celite. The filtrate was then extracted with H₂O 2×,washed brine, dried with sodium sulfate, filtered and concentrated. Theresidue was redissolved in MeOH, filtered and purified by reverse phaseHPLC (PhenomenexLuna AXIA 5 micron C18, 20 min gradient of 0-100% B.A=H₂O/ACN/TFA 90:10:0.1. B=ACN/H₂O/TFA 90:10:0.1) to afford the titlecompound (408b, 38 mg, 0.061 mmol, 13.80% yield). LC-MS (Method A2):1.040 min, [M+H]⁺=509.05.

Example 408:1-((5′-(1H-indol-1-yl)-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid

Example 408 was synthesized from 408b according to the procedure usedfor the synthesis of 403a to afford the title compound (Example 408, 0.7mg, 1.232 μmol, 3.30% yield). MS (ESI) m/z (M+H)⁺=568.4. ¹H NMR (500MHz, DMSO-d₆) δ 7.84-7.66 (m, 5H), 7.58 (s, 1H), 7.51-7.35 (m, J=8.2 Hz,2H), 7.24 (br t, J=7.6 Hz, 1H), 7.16 (t, J=7.3 Hz, 1H), 7.11-6.92 (m,J=8.2 Hz, 2H), 6.74 (d, J=3.4 Hz, 1H), 5.67 (s, 2H), 2.73-2.59 (m, J=7.6Hz, 2H), 1.53 (quin, J=7.6 Hz, 3H), 1.38-1.21 (m, 2H), 0.81 (t, J=7.3Hz, 3H). LC-MS retention time (Method A4): 2.115 min.

Example 409:2-butyl-4-chloro-1-((4″-(dimethylcarbamoyl)-6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 409a:2-butyl-4-chloro-1-((6′-cyano-4″-(dimethylcarbamoyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid, TFA salt

To a pressure-rated vial containing2-butyl-4-chloro-1-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (384b, 200 mg, 0.364 mmol), (4-(dimethylcarbamoyl)phenyl)boronicacid (84 mg, 0.437 mmol) and 2nd generation xphos precatalyst (28.7 mg,0.036 mmol) was added dioxane (1821 μl) followed by 2 M K₃PO₄ (2 M aq)(364 μl, 0.728 mmol). The reaction mixture was sparged with N₂ for 2 minbefore being sealed and heated at 85° C. for 1 h. The reaction mixturewas concentrated onto celite and purified by reverse phase ISCO (30 g 15min gradient of 0-100% B. A=H₂O/ACN/TFA 90:10:0.1. B=ACN/H₂O/TFA90:10:0.1) to afford the title compound (409a, 80 mg, 0.275 mmol, 75%yield). LC-MS: MS (ESI) m/z: 541.4 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.05 (d, J=8.3 Hz, 1H), 7.95-7.89 (m, 4H), 7.69 (d, J=8.3 Hz, 2H), 7.54(d, J=8.3 Hz, 2H), 7.30-7.22 (m, 2H), 5.70 (s, 2H), 3.01 (br s, 3H),2.96 (br s, 3H), 2.70-2.59 (m, 2H), 1.60-1.53 (m, 2H), 1.35-1.23 (m,2H), 0.83 (t, J=7.4 Hz, 3H).

Example 409:2-butyl-4-chloro-1-((4″-(dimethylcarbamoyl)-6′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 409 was synthesized from 409a using the procedure described forthe synthesis of 403a to afford the title compound (Example 409, 5 mg,8.33 μmol, 6.06% yield). MS (ESI) (M+H)⁺=600.0. ¹H NMR (500 MHz,DMSO-d₆) δ 7.91-7.83 (m, 3H), 7.79-7.71 (m, 2H), 7.52 (d, J=8.2 Hz, 2H),7.39 (d, J=7.6 Hz, 2H), 7.10 (br. s., 2H), 5.66 (br. s., 2H), 3.05-2.85(m, 8H), 1.53 (br. s., 2H), 1.27 (d, J=6.7 Hz, 2H), 1.16 (t, J=7.2 Hz,2H). LC-MS retention time (Method A4): 1.674 min

Example 410:2-butyl-1-((6′-carboxy-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-chloro-1H-imidazole-5-carboxylicacid

Example 410a:2-butyl-4-chloro-1-((6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

410a was synthesized from 035a and methyl3-chloro-[1,1′-biphenyl]-4-carboxylate according to the sequencedescribed for the synthesis of 384b. LC-MS (Method A2): 1.00 min,[M+H]⁺=503.05.

Example 410:2-butyl-1-((6′-carboxy-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-chloro-1H-imidazole-5-carboxylicacid

2-butyl-4-chloro-1-((6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (410a, 25 mg, 0.050 mmol) was dissolved in 3:1 THF/MEOH (1 mL). 1MLiOH (0.149 mL, 0.149 mmol) was added and the reaction mixture wasallowed to stir at 60° C. for 18 h. The reaction mixture wasconcentrated, dissolved in DMF, filtered and purified via preparativeLC-MS (XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN:H₂O with 10 mM NH₄OAc; Mobile Phase B: 95:5 ACN: H₂O with 10 mM NH₄OAc;Gradient: 13-53% B over 20 min, then a 6-minute hold at 100% B; Flow: 20mL/min) to afford the title compound (Example 410, 8.4 mg, 0.017 mmol,34.6% yield). MS (ESI) m/z (M+H)⁺=489.1. ¹H NMR (500 MHz, DMSO-d₆) δ7.81 (d, J=7.9 Hz, 1H), 7.73 (d, J=7.6 Hz, 3H), 7.56 (s, 1H), 7.51-7.32(m, 5H), 7.07 (d, J=7.9 Hz, 2H), 5.66 (s, 2H), 2.59 (t, J=7.6 Hz, 2H),1.56-1.44 (m, J=7.6 Hz, 2H), 1.30-1.19 (m, 2H), 0.80 (t, J=7.3 Hz, 3H).LC-MS retention time (Method A4): 2.116 min

Example 411: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylate

1-46′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid, TFA salt (Example 384, 15 mg, 0.024 mmol) was dissolved in DCM (2mL) along with 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (15.56 mg,0.120 mmol). DMAP (14.61 mg, 0.120 mmol) was added followed by EDC(22.93 mg, 0.120 mmol). The reaction mixture was allowed to stir at RTfor 18 h. The reaction mixture was concentrated and purified by ISCO(0-30% MeOH/DCM) to afford the title compound (Example 411, 2.9 mg, 4.41μmol, 18.42% yield). LC-MS (Method A2): 1.09 min, [M+H]⁺=625.1. ¹H NMR(500 MHz, CDCl₃) δ 8.16 (d, J=8.0 Hz, 1H), 7.81 (dd, J=8.1, 1.8 Hz, 1H),7.77-7.73 (m, 1H), 7.71-7.64 (m, 3H), 7.53-7.48 (m, 2H), 7.45 (d, J=7.4Hz, 1H), 7.02 (d, J=8.3 Hz, 2H), 5.57 (s, 2H), 5.07 (s, 2H), 2.73-2.61(m, 2H), 1.79-1.69 (m, 2H), 1.39 (q, J=7.2 Hz, 2H), 1.28 (s, 3H), 0.92(t, J=7.3 Hz, 3H).

Example 412: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-4-ethyl-2-propyl-1H-imidazole-5-carboxylate

Example 412 was synthesized from Example 396 using the proceduredescribed for Example 411 to give the title compound (Example 412, 4.3mg, 6.76 μmol, 13.31% yield). ¹H NMR (500 MHz, CDCl₃) δ 8.16 (d, J=8.3Hz, 1H), 7.83-7.78 (m, 1H), 7.72-7.63 (m, 3H), 7.50 (d, J=7.7 Hz, 2H),7.47-7.40 (m, 1H), 7.25 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.0 Hz, 2H), 5.52(s, 2H), 5.00 (s, 2H), 2.88 (d, J=7.4 Hz, 2H), 2.63-2.52 (m, 2H), 2.21(s, 3H), 1.72 (s, 2H), 1.22 (t, J=7.6 Hz, 3H), 0.97 (t, J=7.4 Hz, 3H).LC-MS (Method A2): 0.89 min, [M+H]⁺=605.2.

Example 413:2-(1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-1H-imidazol-5-yl)-5-methyl-1,3,4-oxadiazole

Intermediate 413a:N′-acetyl-2-butyl-1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carbohydrazide

2-butyl-1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (Example 345, 72 mg, 0.132 mmol) was dissolved in DMF (2 mL).Acetohydrazide (68.6 mg, 0.926 mmol) was added followed by HATU (151 mg,0.397 mmol) and Hunig's Base (0.115 mL, 0.661 mmol). The reactionmixture was allowed to stir for 1 h at RT and was then diluted withEtOAc, washed with 10% LiCl 3×, brine, dried with sodium sulfate,filtered and concentrated. The residue was purified by ISCO (0-25% MeOHin methylene chloride) to afford the title compoundN′-acetyl-2-butyl-1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carbohydrazide(413a, 51 mg, 0.104 mmol, 78% yield). LC-MS: MS (ESI) m/z: 492.5 (M+H)⁺.¹H NMR (500 MHz, CDCl₃) δ 7.80 (d, J=8.0 Hz, 1H), 7.72 (s, 1H),7.69-7.58 (m, 4H), 7.57-7.42 (m, 5H), 7.29 (s, 1H), 7.14 (d, J=8.3 Hz,2H), 5.62 (s, 2H), 2.67 (br t, J=7.7 Hz, 2H), 1.98 (s, 3H), 1.67 (br s,2H), 1.39-1.21 (m, 2H), 0.87 (t, J=7.3 Hz, 3H).

Intermediate 413b:4″-((2-butyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-imidazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

N′-acetyl-2-butyl-1-((6′-cyano-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carbohydrazide(413a, 51 mg, 0.104 mmol) was dissolved in POCl₃ (1 mL) and the reactionmixture was stirred at 100° C. for 30 min. The reaction mixture wascarefully poured into a mixture of ice and 1.5M dipotassium phosphate.The solution was extracted with EtOAc (3×). The combined organic phasewas washed with brine, dried with sodium sulfate, filtered andconcentrated. The crude residue was purified by ISCO (100% EtOAc inhexanes) to afford the title compound (413b, 18 mg, 0.038 mmol, 36.6%yield). LC-MS: MS (ESI) m/z: 474.5 (M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.02 (d, J=8.0 Hz, 1H), 7.92-7.80 (m, 4H), 7.71-7.65 (m, 3H), 7.53-7.49(m, J=7.7 Hz, 2H), 7.48-7.43 (m, 1H), 7.20 (d, J=8.0 Hz, 2H), 5.85 (s,2H), 2.74-2.61 (m, J=7.6, 7.6 Hz, 2H), 2.00 (s, 3H), 1.69-1.53 (m, 2H),1.37-1.25 (m, J=7.4 Hz, 2H), 1.18 (t, J=7.2 Hz, 3H).

Example 413:2-(1-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2-butyl-1H-imidazol-5-yl)-5-methyl-1,3,4-oxadiazole

Example 413 was synthesized from 413b according to the procedure used tosynthesize Example 345. The crude residue was purified by reverse phaseHPLC (Xbridge Prep Shield RP18, 15 min gradient of 20-100% B. A=H₂O/MeOH10 mM NH₄OAc 90:10. B═H₂O/MeOH 10 mM NH₄OAc 10:90) to afford the titlecompound (Example 413, 9.1 mg, 0.018 mmol, 34.8% yield). MS (ESI) m/z(M+H)⁺=517.5. ¹H NMR (500 MHz, DMSO-d₆) δ 7.75 (br. s., 3H), 7.67 (d,J=8.0 Hz, 1H), 7.65-7.56 (m, 2H), 7.48 (t, J=7.5 Hz, 2H), 7.44-7.31 (m,1H), 7.14 (d, J=8.0 Hz, 2H), 6.93 (d, J=8.0 Hz, 2H), 5.71 (br. s., 2H),2.62 (t, J=7.5 Hz, 2H), 2.55 (s, 3H), 1.62-1.44 (m, J=5.8 Hz, 2H),1.30-1.16 (m, 2H), 0.83-0.72 (m, 3H). LC-MS retention time (Method A4):1.551 min.

Example 414:2-butyl-1-((6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-H-imidazole-5-carboxylicacid

Intermediate 414a:2-butyl-1-((6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 414a was synthesized from 345a according to the samesequence used to synthesize 410a. LC-MS (Method A2): 0.850 min,[M+H]⁺=469.10.

Example 414:2-butyl-1-((6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-H-imidazole-5-carboxylicacid

2-Butyl-1-((6′-(methoxycarbonyl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (414a, 35 mg, 0.075 mmol) was dissolved in DMF (2 mL).2-aminoethanol (22.81 mg, 0.373 mmol) was added followed by HATU (85 mg,0.224 mmol) and Hunig's Base (0.065 mL, 0.373 mmol). The reaction wasallowed to stir for 18 h. The reaction mixture was diluted with EtOAc,washed with 10% LiCl 3×, brine, dried with sodium sulfate, filtered andconcentrated. The crude residue was dissolved in 1:1 MeOH/1N NaOH (2 mL)and stirred at 80° C. for 1 h. The reaction mixture was concentrated,dissolved in DMF, filtered and purified by reverse phase HPLC (XbridgePrep Shield RP18, 15 min gradient of 20-100% B. A=H₂O/MeOH 10 mM NH₄OAc90:10. B═H₂O/MeOH 10 mM NH₄OAc 10:90) to afford the title compound(Example 414, 1.7 mg, 0.0034 mmol, 4.60%). MS (ESI) m/z (M+H)⁺=498.4. ¹HNMR (500 MHz, DMSO-d₆) δ 8.25 (br. s., 1H), 7.73 (d, J=7.4 Hz, 2H), 7.66(br. s., 2H), 7.59 (s, 1H), 7.52 (s, 1H), 7.47 (t, J=7.6 Hz, 2H),7.44-7.35 (m, 3H), 7.03 (d, J=7.9 Hz, 2H), 5.67 (s, 2H), 3.64-3.41 (m,2H), 3.32-3.20 (m, J=5.9 Hz, 2H), 2.61-2.56 (m, 2H), 1.63-1.46 (m, 2H),1.37-1.19 (m, 2H), 1.00 (d, J=6.2 Hz, 1H), 0.82 (t, J=7.3 Hz, 3H). LC-MSretention time (Method A4): 1.703 min.

Example 415:2-butyl-1-((6′-carboxy-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 415 was synthesized from 345a according to the same sequenceused to synthesize Example 410. MS (ESI) m/z (M+H)⁺=454.9. ¹H NMR (500MHz, DMSO-d₆) δ 7.80-7.66 (m, 4H), 7.56-7.43 (m, 4H), 7.42-7.32 (m, 3H),7.04 (d, J=7.8 Hz, 2H), 5.69 (br. s., 2H), 2.61-2.56 (m, 2H), 1.50(quin, J=7.4 Hz, 2H), 1.29-1.13 (m, 2H), 0.78 (t, J=7.3 Hz, 3H). LC-MSretention time (Method A4): 1.731 min

Example 416:2-butyl-4-chloro-1-((5′-(3,3-difluoropiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 416a:2-butyl-4-chloro-1-((2′-cyano-5′-(3,3-difluoropiperidin-1-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid, TFA salt

416a was synthesized from 3,3-difluoropiperidine hydrochloride accordingto the procedure used to synthesize 405a to give the title compound(416a, 130 mg, 0.207 mmol, 56.9% yield). LC-MS: MS (ESI) m/z: 513.10(M+H)⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 7.66 (d, J=8.8 Hz, 1H), 7.55 (d,J=8.3 Hz, 2H), 7.26 (t, J=7.3 Hz, 2H), 7.21-7.07 (m, 2H), 7.02 (d, J=2.8Hz, 1H), 5.67 (s, 2H), 3.81 (br t, J=12.0 Hz, 2H), 3.55-3.34 (m, 2H),2.69-2.57 (m, 2H), 2.13-2.04 (m, 2H), 1.75 (br d, J=4.4 Hz, 2H), 1.56(br t, J=7.6 Hz, 2H), 1.35-1.20 (m, 2H), 0.83 (t, J=7.3 Hz, 3H).

Example 416:2-butyl-4-chloro-1-((5′-(3,3-difluoropiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 416 was synthesized from 416a according to the proceduredescribed for Example 345. The crude mixture was purified by reversephase HPLC (Xbridge Prep Shield RP18, 15 min gradient of 20-100% B.A=H₂O/MeOH 10 mM NH₄OAc 90:10. B=H₂O/MeOH 10 mM NH₄OAc 10:90) to affordthe title compound (Example 416, 4.2 mg, 7.55 μmol, 9.01% yield). MS(ESI) m/z (M+H)⁺=556.0. ¹H NMR (500 MHz, DMSO-d₆) δ 7.43 (d, J=8.5 Hz,1H), 7.07 (br d, J=7.9 Hz, 3H), 6.89 (br d, J=7.6 Hz, 3H), 5.65 (s, 2H),3.32 (br s, 1H), 2.87 (q, J=7.0 Hz, 1H), 2.52 (br s, 2H), 2.12-1.97 (m,2H), 1.91 (s, 1H), 1.79 (br s, 2H), 1.50 (quin, J=7.5 Hz, 2H), 1.13 (s,4H), 0.82 (t, J=7.3 Hz, 3H. LC-MS retention time (Method A4): 1.810 min

Example 417:1-((5′-(1H-indol-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylicacid

Example 417 was synthesized from indoline and 384b according to thesequence described for Example 416. The crude mixture was purified byreverse phase HPLC (Xbridge Prep Shield RP18, 15 min gradient of 20-100%B. A=H₂O/MeOH 10 mM NH₄OAc 90:10. B═H₂O/MeOH 10 mM NH₄OAc 10:90) toafford the title compound2-butyl-4-chloro-1-((5-(3,3-difluoropiperidin-1-yl)-2′-(2H-tetrazol-5-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (416, 4.2 mg, 7.55 μmol, 9.01% yield). MS (ESI) m/z (M+H)⁺=552.2.¹H NMR (500 MHz, DMSO-d₆) δ 7.80-7.71 (m, 2H), 7.71-7.58 (m, 3H), 7.44(s, 1H), 7.25-7.11 (m, 4H), 6.90 (br d, J=7.9 Hz, 2H), 6.71 (d, J=3.1Hz, 1H), 5.69 (br s, 2H), 2.56-2.53 (m, 2H), 1.54-1.42 (m, 2H),1.32-1.18 (m, 2H), 0.78 (t, J=7.3 Hz, 3H). LC-MS retention time (MethodA4): 2.063 min

Example 418:(S)-2-butyl-4-chloro-1-((5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 418a:(S)-2-butyl-4-chloro-1-((5′-(3-methylpiperidin-1-yl)-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carbaldehyde

To a small vial containing(S)-4′-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-(3-methylpiperidin-1-yl)-[1,1′-biphenyl]-2-carbonitrile(407b, 90 mg, 0.189 mmol) was added dibutyltin oxide (47.2 mg, 0.189mmol) and toluene (1 mL) followed by TMS-N₃ (0.126 mL, 0.947 mmol). Thereaction mixture was sealed and heated at 100° C. for 20 hours. Thereaction mixture was concentrated to dryness. The crude residue wasdissolved in DCM (2 mL). TEA (0.086 mL, 0.615 mmol) was added followedby trityl-Cl (129 mg, 0.461 mmol). The reaction mixture was allowed tostir at RT for 2 h. The reaction mixture was then diluted with DCM,washed with 1.5M dipotassium phosphate, brine, dried with sodiumsulfate, filtered and concentrated. The product was brought forwardwithout further purification. LC-MS (Method A2): 1.20 min, [M+H]⁺=760.3.

Intermediate 418b:(S)-2-butyl-4-chloro-1-((5′-(3-methylpiperidin-1-yl)-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

418b was synthesized from 418a according to the same procedure describedfor 345c. The product was brought forward without further purification.LC-MS (Method A2): 1.16 min, [M+H]⁺=776.08.

Example 418:(S)-2-butyl-4-chloro-1-((5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 418 was prepared from 418b according to the same proceduredescribed for Example 384. The crude mixture was purified by reversephase HPLC (Xbridge Prep Shield RP18, 15 min gradient of 20-100% B.A=H₂O/MeOH 10 mM NH₄OAc 90:10. B=H₂O/MeOH 10 mM NH₄OAc 10:90) to affordthe title compound (Example 418, 7.3 mg, 0.014 mmol, 14.60% yield). MS(ESI) m/z (M+H)⁺=534.1. ¹H NMR (500 MHz, DMSO-d₆) δ 7.44 (d, J=8.6 Hz,1H), 7.15-7.04 (m, J=8.0 Hz, 2H), 7.00 (dd, J=8.6, 2.3 Hz, 1H),6.96-6.90 (m, J=7.9 Hz, 2H), 6.83 (d, J=2.2 Hz, 1H), 5.64 (s, 2H),2.79-2.65 (m, 2H), 2.57-2.53 (m, 2H), 2.47-2.35 (m, 1H), 1.71 (br dd,J=9.9, 3.3 Hz, 3H), 1.63-1.46 (m, 3H), 1.36-1.22 (m, 3H), 1.09 (br dd,J=11.5, 3.2 Hz, 1H), 0.93 (d, J=6.6 Hz, 3H), 0.83 (t, J=7.3 Hz, 3H.LC-MS retention time (Method A4): 1.780 min.

Example 419:(R)-2-butyl-4-chloro-1-((5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 419 was synthesized from (R)-3-methylpiperidine hydrochlorideusing the same sequence described for Example 418. The crude mixture waspurified by reverse phase HPLC: Column: XBridge C18, 19×200 mm, 5-μmparticles; Mobile Phase A: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid;Mobile Phase B: 95:5 ACN: H₂O with 0.1% trifluoroacetic acid; Gradient:26-66% B over 20 min, then a 4-minute hold at 100% B; Flow: 20 mL/min toafford the title compound(R)-2-butyl-4-chloro-1-((5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (Example 419, 1.7 mg, 3.18 mol, 8.23% yield). LC-MS (Method A2):1.811 min, [M+H]⁺=534.4. ¹H NMR (500 MHz, DMSO-d₆) δ 7.45 (d, J=8.5 Hz,1H), 7.14-7.02 (m, J=7.9 Hz, 3H), 6.95 (br d, J=7.9 Hz, 2H), 6.87 (s,1H), 5.60 (s, 2H), 3.79 (br t, J=13.7 Hz, 1H), 3.40-3.23 (m, 1H),3.21-3.12 (m, 1H), 2.79-2.64 (m, 1H), 2.49-2.31 (m, 2H), 1.77 (br d,J=10.4 Hz, 1H), 1.73-1.61 (m, 2H), 1.60-1.40 (m, 4H), 1.31-1.16 (m, 2H),1.01 (d, J=6.4 Hz, 3H), 0.88-0.74 (m, 3H).

Example 420:(S)-2-butyl-4-chloro-1-((5′-(3-methylpiperidin-1-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)me

To a pressure-rated vial containing2-butyl-4-chloro-1-((5′-chloro-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (384d, 65 mg, 0.091 mmol), 2nd generation xphos precatalyst (14.33mg, 0.018 mmol) and bis(pinacolato)diborane (34.7 mg, 0.137 mmol) wasadded dioxane (2 mL) followed by KOAc (44.7 mg, 0.455 mmol). Thereaction mixture was evacuated and backfilled with N₂ (3×) then heatedat 85° C. for 18 h. To the reaction mixture was then added additional2nd generation xphos precatalyst (14.33 mg, 0.018 mmol) as well as2-bromo-4-methylpyridine (94 mg, 0.546 mmol) and2-bromo-4-methylpyridine (94 mg, 0.546 mmol). The reaction mixture wasevacuated and backfilled with N₂ (3×) then allowed to stir at 85° C. for18 h. The reaction mixture was diluted with EtOAc, filtered throughcelite. The filtrate was concentrated then redissolved in DCM (2 mL).Triethylsilane (0.145 mL, 0.911 mmol) was added followed by TFA (0.351mL, 4.55 mmol). The reaction mixture was allowed to stir at RT for 30min. The mixture was then concentrated, dissolved in DMF, filtered andpurified by reverse phase HPLC (Xbridge Prep Shield RP18, 15 mingradient of 20-100% B. A=H₂O/MeOH 10 mM NH₄OAc 90:10. B═H₂O/MeOH 10 mMNH₄OAc 10:90) to afford the title compound (2.2 mg, 4.17 μmol, 4.57%yield). MS (ESI) (M−H)⁻=525.9. ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (d,J=4.9 Hz, 1H), 8.24 (br d, J=7.9 Hz, 1H), 8.01 (s, 1H), 7.78 (d, J=8.2Hz, 1H), 7.33-7.27 (m, 2H), 7.21-7.14 (m, 3H), 6.99 (br d, J=7.9 Hz,2H), 5.60 (s, 2H), 2.61-2.56 (m, 2H), 2.42 (s, 3H), 1.50 (br t, J=7.3Hz, 2H), 1.30-1.19 (m, 2H), 0.81 (t, J=7.3 Hz, 3H. LC-MS retention time(Method A4): 1.409 min

Example 421:2-butyl-4-chloro-1-((5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 421 was prepared according to the same procedure as describedfor Example 420 to give the title compound (Example 421, 0.5 mg, 0.00092mmol, 1.5%). MS (ESI) m/z (M+H)⁺=544.1. ¹H NMR (500 MHz, DMSO-d₆) δ 8.48(d, J=5.5 Hz, 1H), 8.13 (br d, J=7.9 Hz, 1H), 8.06 (s, 1H), 7.72 (d,J=7.9 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.18 (br d, J=8.2 Hz, 2H),7.07-6.87 (m, 3H), 5.63 (br s, 2H), 3.93 (s, 3H), 1.61-1.44 (m, 2H),1.34-1.20 (m, 2H), 0.84 (t, J=7.3 Hz, 3H). LC-MS retention time (MethodA4): 1.235 min

Example 422:2-butyl-4-chloro-1-((5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 422a:2-butyl-4-chloro-1-((5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

To a pressure-rated vial containing2-butyl-4-chloro-1-((5′-chloro-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (384d, 0.615 g, 0.862 mmol), bis(pinacolato)diborane (0.438 g,1.724 mmol) Pd₂(dba)₃ (79 mg, 0.086 mmol) was added dioxane (7 ml)followed by KOAc (0.423 g, 4.31 mmol). The reaction mixture wasevacuated and backfilled with N₂ (3×) and heated at 105° C. for 40 min.The reaction mixture was then diluted with EtOAc and filtered throughcelite. The filtrate was then concentrated and the crude residue wassuspended in hexanes. The filtered off solid was purified by ISCO (0-20%MeOH/DCM) to afford the title compound (0.7 g, 0.869 mmol, 50.4% yield).LC-MS (Method A2): 1.24 min, [M+H]⁺=805.4.

Example 422:2-butyl-4-chloro-1-((5′-(4-(dimethylamino)pyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

To a vial containing 2-bromo-N,N-dimethylpyridin-4-amine (6.49 mg, 0.032mmol) was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(ii)(XPhos Pd G2) (5.08 mg, 6.46 μmol) followed by2-butyl-4-chloro-1-((5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2′-(2-trityl-2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (422a, 0.064M in dioxane, 0.497 mL, 0.032 mmol) and tripotassiumphosphate (0.042 mL, 0.084 mmol). The vial was evacuated and backfilledwith Ar (2×), sealed with septa caps and stirred at 105° C. for 2 h. Thereaction mixture was filtered and dissolved in DCM (0.5 mL).Triethylsilane (0.022 mL, 0.136 mmol) and TFA (0.095 mL, 1.227 mmol)were added. The resulting reaction mixture was then stirred at RT for 1h then concentrated, dissolved in DMF, filtered and purified by reversephase HPLC (Xbridge Prep Shield RP18, 15 min gradient of 20-100% B.A=H₂O/MeOH 10 mM NH₄OAc 90:10. B═H₂O/MeOH 10 mM NH₄OAc 10:90) to affordthe title compound (Example 422, 0.7 mg, 0.0012 mmol, 3.9%). LC-MS(Method A4): 1.279 min, [M+H]⁺=557.2; ¹H NMR (500 MHz, DMSO-d₆) δ 8.21(d, J=5.8 Hz, 1H), 8.02 (br d, J=7.9 Hz, 1H), 7.94 (s, 1H), 7.65 (br d,J=8.2 Hz, 1H), 7.12 (br d, J=7.0 Hz, 3H), 6.91 (br d, J=7.6 Hz, 2H),6.60 (br d, J=5.8 Hz, 1H), 5.76 (br s, 2H), 2.49-2.39 (m, 2H), 1.91 (s,6H), 1.51 (br t, J=7.0 Hz, 2H), 1.30-1.13 (m, 2H), 0.90-0.74 (m, 3H).

Example 423:2-butyl-4-chloro-1-((5′-(6-(difluoromethyl)pyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 423 was synthesized from 2-bromo-6-(difluoromethyl)pyridineusing the same procedure described for Example 422 to give the titlecompound (2.3 mg, 0.0041 mmol, 12.8%). LC-MS (Method A4): 1.379 min,[M+H]⁺=564.1; ¹H NMR (500 MHz, DMSO-d₆) δ 8.29 (br d, J=7.9 Hz, 1H),8.21 (br d, J=7.9 Hz, 1H), 8.17-8.08 (m, 2H), 7.81 (br d, J=8.2 Hz, 1H),7.70 (br d, J=7.6 Hz, 1H), 7.18 (br d, J=7.9 Hz, 2H), 7.16-6.91 (m,J=55.1, 55.1 Hz, 1H), 6.97 (br d, J=7.6 Hz, 2H), 5.62 (br s, 2H),1.59-1.48 (m, 2H), 1.33-1.14 (m, 4H), 0.84 (br t, J=7.3 Hz, 3H).

Example 424:2-butyl-4-chloro-1-((5′-cyclohexyl-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 424a: lithium2-butyl-4-chloro-1-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylate

2-butyl-4-chloro-1-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (384b, 2 g, 4.67 mmol) was dissolved in Tetrahydrofuran (20 mL). 1MLiOH (5.14 mL, 5.14 mmol) was added and the reaction was allowed to stirat RT for 30 min. The reaction was concentrated to dryness andazeotroped with toluene (3×) to yield the title compound. The productwas brought forward without further purification. LC-MS (Method A2):0.96 min, [M+H]⁺=428.0;

Intermediate 424b:2-butyl-4-chloro-1-((6′-cyano-2″,3″,4″,5″-tetrahydro-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Lithium2-butyl-4-chloro-1-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylate(424a, 200 mg, 0.461 mmol), cyclohex-1-en-1-ylboronic acid (69.6 mg,0.553 mmol), 2nd generation xphos precatalyst (36.2 mg, 0.046 mmol) and2M K₃PO₄ (0.461 mL, 0.921 mmol) were dissolved in dioxane (2 mL). Thereaction mixture was evacuated and backfilled with N₂ (3×) then heatedat 85° C. for 1 hour. The reaction mixture was diluted with EtOAc andconcentrated onto celite and purified by ISCO (0-20% MeOH/DCM) to affordthe title compound2-butyl-4-chloro-1-46′-cyano-2″,3″,4″,5″-tetrahydro-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (424b, 200 mg, 0.139 mmol, 30.2% yield). LC-MS (Method A2): 1.11min, [M+H]⁺=474.0;

Intermediate 424c:2-butyl-4-chloro-1-((2′-cyano-5′-cyclohexyl-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

2-butyl-4-chloro-1-((6′-cyano-2″,3″,4″,5″-tetrahydro-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (424b, 200 mg, 0.127 mmol) was dissolved in MeOH (15 mL). Pd—C(26.9 mg, 0.025 mmol) was added and the reaction mixture was evacuatedand backfilled with 1 atm of H₂. The reaction mixture was allowed tostir at RT for 60 min. The reaction mixture was then evacuated andbackfilled with N₂ (3×) then filtered through celite. The filtrate wasconcentrated and purified by Prep HPLC (0-100% A/B 10 minute gradientSolvent A: 10% ACN—90% H₂O—0.1% TFA, Solvent B: 90% ACN—10% H₂O—0.1% TFAVial: 51 Column: 2: Phenomenex Luna Axia 5 u 30×100 (10 min grad)) toafford the title compound (424c, 38 mg, 0.080 mmol, 63.1% yield). LC-MS(Method A2): 1.12 min, [M+H]⁺=476.0;

Example 424:2-butyl-4-chloro-1-((5′-cyclohexyl-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Example 424 was synthesized from 424c using the procedure described forExample 345. The crude residue was purified by reverse phase HPLC(Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95ACN: H₂O with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂Owith 0.1% trifluoroacetic acid; Gradient: 42-82% B over 20 min, then a6-minute hold at 100% B; Flow: 20 mL/min) to afford the title compound2-butyl-4-chloro-1-((5′-cyclohexyl-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (Example 424, 4.0 mg, 7.71 mol, 23.93% yield). MS (ESI) m/z(M+H)⁺=519.1. ¹H NMR (500 MHz, DMSO-d₆) δ 7.56 (br d, J=7.9 Hz, 1H),7.43 (br d, J=7.6 Hz, 1H), 7.34 (br s, 1H), 7.08 (br d, J=7.3 Hz, 2H),6.96 (br d, J=7.9 Hz, 2H), 5.60 (s, 2H), 1.89-1.82 (m, J=13.1 Hz, 3H),1.80 (br s, 1H), 1.71 (br s, 1H), 1.55-1.34 (m, 7H), 1.33-1.16 (m, 4H),0.82 (t, J=7.3 Hz, 4H. LC-MS retention time (Method A4): 2.192 min

The compounds in the following table are prepared using the methods forExample 396 and Example 398, respectively:

LC-MS m/z [M + H]⁺; RT ¹H NMR (500 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 425

506.61 507.23; 1.55 min (Method A4) 7.94-7.83 (m, 2H), 7.80 (br d, J =7.3 Hz, 2H), 7.62 (s, 1H), 7.54- 7.40 (m, 3H), 7.17-7.02 (m, 2H), 7.00(s, 1H), 6.81 (br d, J = 7.6 Hz, 1H), 5.67 (br s, 2H), 2.91 (q, J = 7.3Hz, 2H), 1.96 (s, 3H), 1.58-1.49 (m, 2H), 1.21 (t, J = 7.5 Hz, 3H), 0.86(t, J = 7.3 Hz, 3H). 426

505.63 506.2; 1.51 min (Method A4) 7.88 (d, J = 7.9 Hz, 1H), 7.79-7.70(m, 3H), 7.47 (t, J = 7.5 Hz, 2H), 7.43 (s, 1H), 7.41-7.31 (m, 3H), 7.00(d, J = 7.6 Hz, 1H), 6.90 (s, 1H), 6.77 (br d, J = 7.9 Hz, 1H), 5.39 (s,2H), 2.68 (q, J = 7.3 Hz, 2H), 1.89 (s, 3H), 1.62-1.54 (m, 2H), 1.15 (t,J = 7.5 Hz, 3H), 0.88 (t, J = 7.3 Hz, 3H).

Example 427:2-Butyl-4-chloro-1-((5′-(pyridin-2-yloxy)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

Intermediate 427a:4′-((2-Butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-hydroxy-[1,1′-biphenyl]-2-carbonitrile

The title compound was obtained from2-butyl-4-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carbaldehyde(Intermediate 35a) and 2-bromo-4-hydroxybenzonitrile, according to theprocedure described for the synthesis of Intermediate 247a. LC-MS(Method H): 1.26 min, [M+H]⁺=394.0. HRMS (ESI): Calcd. for C₂₂H₂₁ClN₃O₂[M+H]+m/z 394.1317; found 394.1294.

Intermediate 427b:4′-((2-Butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-(pyridin-2-yloxy)-[1,1′-biphenyl]-2-carbonitrile

The title compound was prepared from4′-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-hydroxy-[1,1′-biphenyl]-2-carbonitrile(Intermediate 427a) and 2-chloropyridine, according to the methoddescribed for the synthesis of Example 247. LC-MS (Method H): 1.36 min,[M+H]⁺=471.1. HRMS (ESI): Calcd. for C₂₇H₂₄ClN₄O₂ [M+H]⁺ m/z 471.1582;found 471.1577.

Intermediate 427c:2-Butyl-4-chloro-1-((2′-cyano-5′-(pyridin-2-yloxy)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

4′-((2-Butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-(pyridin-2-yloxy)-[1,1′-biphenyl]-2-carbonitrilewas converted to the title compound using an oxidation procedure similarto that described for the synthesis of 345b. LC-MS (Method H): 1.44 min,[M+H]⁺=487.1. HRMS (ESI): Calcd. for C₂₇H₂₄ClN₄O₃ [M+H]⁺ m/z 487.1531;found 487.1537. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.22 (m, 1H), 7.98 (d,J=8.2 Hz, 1H), 7.93 (m, 1H), 7.58 (d, J=8.2 Hz, 2H) 7.34 (m, 2H), 7.21(m, 1H), 7.15 (m, 3H), 5.67 (s, 2H), 2.62 (t, J=7.2 Hz, 2H), 1.51 (m,2H), 1.19 (m, 2H), 0.79 (t, J=7.2 Hz, 3H).

Example 427:2-Butyl-4-chloro-1-((5′-(pyridin-2-yloxy)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid

The title compound was prepared from2-butyl-4-chloro-1-((2′-cyano-5′-(pyridin-2-yloxy)-[1,1′-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylicacid (Intermediate 427c), according to the procedure described for thesynthesis of Example 345. LC-MS (Method H): 1.29 min, [M+H]⁺=530.1. HRMS(ESI): Calcd. for C₂₇H₂₄ClN₇O₃ [M+H^(])+m/z 530.1702; found 530.1688. ¹HNMR (400 MHz, MeOH-d₄) δ ppm 8.19 (m, 1H), 7.89 (m, 1H), 7.72 (d, J=8.6Hz, 1H), 7.28 (m, 2H), 7.19 (m, 1H), 7.11 (m, 3H), 7.00 (d, J=7.8 Hz,2H), 5.65 (s, 2H), 2.64 (t, J=7.8 Hz, 2H), 1.56 (m, 2H), 1.30 (m, 2H),0.87 (t, J=7.5 Hz, 3H).

The following examples have been similarly prepared from4′-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-hydroxy-[1,1′-biphenyl]-2-carbonitrile(Intermediate 427a) and 2-chloro-4-methylpyridine or from4′-((2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile[obtained from2-butyl-4-chloro-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1H-imidazole-5-carbaldehyde(Intermediate 35a) and 2-bromo-4-fluorobenzonitrile, according to theprocedure described for the synthesis of Intermediate 247a] and3-hydroxypyridine, using the procedures described above.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW (MethodH) δ ppm 428

529.98 530.10; 1.24 min (MeOH-d₄): 8.41 (br. s, 1H), 8.37 (m, 1H), 7.70(d, J = 8.6 Hz, 1H), 7.65 (m, 1H), 7.50 (m, 1H), 7.22 (m, 2H), 7.11 (d,J = 7.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 5.65 (s, 2H), 2.61 (t, J =7.8 Hz, 2H), 1.56 (m, 2H), 1.30 (m, 2H), 0.87 (t, J = 7.5 Hz, 3H)

Example 430:(S)-2-(N-((6-(4-(2H-Tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)-3-methylbutanoicacid

Intermediate 430a: (S)-Methyl2-(((6-bromopyridin-3-yl)methyl)amino)-3-methylbutanoate

To a mixture of 6-bromopicolinaldehyde (5.02 g, 27.0 mmol), (S)-methyl2-amino-3-methylbutanoate hydrochloride (4.52 g, 27.0 mmol) and sodiumacetate (4.43 g, 54.0 mmol) in MeOH (500 mL) was added 4 Å molecularsieves (25 g) and the mixture was stirred at RT for 30 min. To thismixture was then added sodium cyanoborohydride (3.39 g, 54.0 mmol) andthe mixture stirred at RT for 18 h. The pH of the mixture was thenadjusted, first to ca.2 by the addition of 4M HCl (25 mL) and then to pHca.10 with 2M Na₂CO₃ (25 mL). The resulting suspension was filtered andthe filter-cake was washed with small amounts of MeOH. The combinedfiltrate was concentrated under reduced pressure and the concentrate wasextracted with tert-butylmethyl ether (200 mL). The organic extract waswashed with washed with brine, dried over anhydrous sodium sulfate,filtered and evaporated. The residue obtained was purified by flashchromatography using an 80 gram ISCO-type column and a 0 to 30%EtOAc/hexane gradient to afford the title compound as a clear colorlessoil (7.50 g, 24.9 mmol, 92% yield). LC-MS (Method H): 1.07 min,[M+H]⁺=301.1; ¹H NMR (DMSO-d₆) δ ppm 8.27-8.31 (m, 1H), 7.69 (dd, J=8.2,2.7 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 3.76 (d, J=14.1 Hz, 1H), 3.61 (s,3H), 3.51 (d, J=14.1 Hz, 1H), 2.87 (br s, 1H), 2.59 (br s, 1H), 1.83(dq, J=13.6, 6.7 Hz, 1H), 0.89 (d, J=7.0 Hz, 3H), 0.84 (d, J=7.0 Hz,3H).

Intermediate 430b: (S)-Methyl2-(N-((6-bromopyridin-3-yl)methyl)pentanamido)-3-methylbutanoate

To a mixture of (S)-methyl2-(((6-bromopyridin-3-yl)methyl)amino)-3-methylbutanoate (5.30 g, 17.6mmol) and potassium carbonate (7.30 g, 52.8 mmol) in ACN (50 mL) wasadded pentanoyl chloride (5.22 mL, 44.0 mmol) dropwise over about 5 minand the mixture was then stirred at RT for 2 h. The resulting mixturewas then diluted with H₂O (50 mL) and the mixture was concentrated tohalf-volume under reduced pressure. The aqueous concentrate wasextracted with tert-butylmethyl ether (150 mL) and the organic phase wasseparated, washed (10% aqueous citric acid ×3, saturated aqueous Na₂CO₃,and brine), dried over anhydrous sodium sulfate, filtered andevaporated. The residue obtained was purified by flash chromatography ona 40 g Icso-type column using a 10 to 30% EtOAc/hexane gradient toprovide the title compound as a white solid (4.69 g, 12.3 mmol, 69%yield). LC-MS (Method H): 1.27 min, [M+H]⁺=385.1; ¹H NMR (DMSO-d6) δ ppm8.27 (d, J=2.3 Hz, 0.5H), 8.14 (d, J=2.3 Hz, 0.5H), 7.62-7.68 (m, 0.5H),7.52-7.61 (m, 1H), 7.46 (dd, J=8.2, 2.3 Hz, 0.5H), 4.67-4.76 (m, 1H),4.56-4.67 (m, 0.5H), 4.44 (d, J=9.8 Hz, 0.5H), 4.17-4.28 (m, 1H), 3.40(s, 1.5H), 3.39 (s, 1.5H), 2.40-2.58 (m, 1H), 2.24-2.38 (m, 1.5H),2.12-2.23 (m, 0.5H), 1.38-1.62 (m, 2H), 1.13-1.38 (m, 2H), 0.70-0.99 (m,9H).

Intermediate 430c: (S)-Methyl2-(N-((6-(4-cyano-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)-3-methylbutanoate

The title compound was prepared by the reaction of (S)-methyl2-(N-((6-bromopyridin-3-yl)methyl)pentanamido)-3-methylbutanoate (0.075g, 0.195 mmol) with3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-4-carbonitrile(Intermediate 268c, 0.068 g, 0.234 mmol), according to the methoddescribed for the synthesis of Intermediate 330b, to give a white solid(0.083 g, 0.172 mmol, 88% yield). LC-MS (Method H): 1.36 min,[M+H]⁺=484.2; ¹H NMR (DMSO-d₆) δ ppm 8.62 (s, 0.5H), 8.49 (s, 0.5H),8.08-8.15 (m, 1H), 7.98-8.08 (m, 1.5H), 7.89-7.98 (m, 1.5H), 7.77-7.89(m, 2.5H), 7.64-7.71 (m, 0.5H), 7.42-7.58 (m, 3H), 4.89 (dd, J=16.8,13.3 Hz, 1H), 4.73 (d, J=16.8 Hz, 0.5H), 4.56 (d, J=10.2 Hz, 1H),4.24-4.35 (m, 0.5H), 3.41 (s, 1.5H), 3.37 (s, 1.5H), 2.52-2.63 (m, 1H),2.17-2.47 (m, 2H), 1.41-1.66 (m, 2H), 1.15-1.41 (m, 2H), 0.76-1.00 (m,9H).

Example 430:(S)-2-(N-((6-(4-(2H-Tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)-3-methylbutanoicacid

The title compound was prepared from (S)-methyl2-(N-((6-(4-cyano-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)-3-methylbutanoateaccording to the method described for the synthesis of Example 283 andwas isolated as an off-white solid. LC-MS (Method H): 1.29 min,[M+H]⁺=513.2; ¹H NMR (DMSO-d₆) δ ppm 12.62 (s, 2H), 8.33 (s, 0.5H), 8.21(s, 0.5H), 7.94-8.00 (m, 1H), 7.86-7.94 (m, 1H), 7.82 (d, J=7.4 Hz,2.5H), 7.75 (t, J=8.0 Hz, 1H), 7.69 (d, J=8.2 Hz, 0.5H), 7.48-7.59 (m,2.5H), 7.37-7.48 (m, 1.5H), 4.68 (s, 1H), 4.48-4.59 (m, 0.5H), 4.31-4.48(m, 1H), 4.09 (m, 0.5H), 2.36-2.46 (m, 1H), 1.99-2.33 (m, 2H), 1.34-1.61(m, 2H), 1.11-1.34 (m, 2H), 0.63-1.01 (m, 9H).

The following examples were similarly prepared according to the methoddescribed for the synthesis of Example 430 above. Analytical LC-MSinjections were used to determine the final purity and the retentiontime is reported for each compound and the method used is referred to asMethod A1, Method A2 or Method H.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 431

512.25 513.2; 1.27 min (Method H) 13.05 (s, 2H), 8.36 (m, 1H), 7.95 (td,J = 8.2, 1.6 Hz, 2H), 7.77-7.91 (m, 4H), 7.60-7.77 (m, 1H), 7.51-7.52(m, 2H),7.39-7.47 (m, 1H), 4.53- 4.96 (m, 2H), 4.15 (dd, J = 9.6, 5.3Hz, 1H), 2.57 (m, 1H), 2.07- 2.37 (m, 2H), 1.13-1.62 (m, 4H), 0.69-0.98(m, 9H). 432

498.24 499.1; 1.27 min (Method H) 13.06 (br s, 1H), 12.61 (br s, 1H),8.35 (s, 0.5H), 8.26 (s, 0.5H), 7.97-8.04 (m, 1H), 7.94 (dt, J = 8.0,2.2 Hz, 1H), 7.85 (d, J = 7.8 Hz, 2H), 7.70-7.82 (m, 1.5H), 7.62 (t, J =6.3 Hz, 1H), 7.49-7.58 (m, 2.5H), 7.40- 7.49 (m, 1H), 4.71 (s, 1H), 4.58(d, J = 15.7 Hz, 0.5H), 4.46 (d, J = 16.0 Hz, 0.5H), 4.39 (d, J = 9.8Hz, 0.5H), 4.12 (d, J = 10.6 Hz, 0.5H), 2.41- 2.52 (m, 1H), 2.02-2.31(m, 2H), 1.36-1.64 (m, 2H), 0.70- 1.01 (m, 9H). 433

526.27 527.2; 1.32 min (Method H) 13.06 (br s, 1H), 12.64 (br s, 1H),8.37 (s, 0.5H), 8.25 (s, 0.5H), 7.99 (br s, 1H), 7.94 (d, J = 7.8 Hz,1H), 7.84 (d, J = 7.4 Hz, 2H), 7.70-7.81 (m, 1.5H), 7.58-7.65 (m, 1H),7.49-7.58 (m, 2.5H), 7.40-7.49 (m, 1H), 4.71 (s, 1H), 4.57 (d, J = 15.7Hz, 0.5H), 4.46 (d, J = 16.0 Hz, 0.5H), 4.39 (d, J = 9.8 Hz, 0.5H), 4.12(d, J = 10.2 Hz, 0.5H), 2.39-2.48 (m, 1H), 2.04- 2.31 (m, 2H), 1.29-1.58(m, 3H), 1.22-1.29 (m, 1.5H), 1.13 (d, J = 6.3 Hz, 1.5H), 0.68- 1.02 (m,9H).

Example 434:(S)-3-Methyl-2-(N-((6-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)butanoicacid 2,2,2-trifluoroacetate

Intermediate 434a: (S)-tert-Butyl2-(N-((6-(4-cyano-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)-3-methylbutanoate

The title compound was prepared from 6-bromonicotinaldehyde and(S)-tert-butyl 2-amino-3-methylbutanoate hydrochloride, according to themethod described for the synthesis of Intermediate 430c and was isolatedas an off-white solid. LC-MS (Method H): 1.49 min, [M+H]⁺=526.2; ¹H NMR(DMSO-d₆) δ ppm 8.86 (m, 0.5H), 8.53 (m, 0.5H), 8.02-8.12 (2.5H),7.82-7.96 (m, 4H), 7.69-7.72 (m, 0.5H), 7.45-7.56 (m, 3H), 4.76-4.86 (m,1.5H), 4.33-4.43 (m, 1H), 4.09-4.11 (m, 0.5H), 2.44-2.85 (m, 1H),2.17-2.40 (m, 2H), 1.31-1.86 (m, 4H), 1.22-1.26 (m, 9H), 0.77-0.98 (m,9H).

Intermediate 434b: (S,Z)-tert-Butyl2-(N-((6-(4-(N′-hydroxycarbamimidoyl)-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)-3-methylbutanoate2,2,2-trifluoroacetate

To a solution of (S)-tert-butyl2-(N-((6-(4-cyano-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)-3-methylbutanoate(0.050 g, 0.095 mmol) in ethanol (2 mL) was added hydroxylaminehydrochloride (0.066 g, 0.952 mmol) and DIEA (0.166 mL, 0.951 mmol). Thereaction vessel was sealed and the mixture heated at 85° C. for 3 h. Thecooled mixture was then evaporated under reduced pressure and theresidue was taken up in DMSO (2.5 mL) and formic acid (0.125 mL) wasadded. The mixture was purified by prep LC (Method F, TFA as modifier)to afford the title compound (as TFA salt) as a white solid (52 mg,0.077 mmol, 81% yield). LC-MS (Method H): 1.41 min, [M+H]⁺=559.3; HRMS(ESI): Calcd for C₃₃H₄₃N₄O₄ [M+H]⁺ m/z 559.3279; found 559.3281.

Example 434:(S)-3-Methyl-2-(N-((6-(4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)butanoicacid 2,2,2-trifluoroacetate

To a solution of (S,Z)-tert-butyl2-(N-((6-(4-(N′-hydroxycarbamimidoyl)-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)pentanamido)-3-methylbutanoate.TFA(0.050 g, 0.074 mmol) in THF (2 mL) was added DBU (0.057 g, 0.372 mmol)and N,N′-carbonyldiimidazole (0.060 g, 0.372 mmol) and the mixture wasstirred in a sealed vial at 50° C. for 2 h. The cooled mixture was thenevaporated, trifluoroacetic acid (1 mL) was added to the residue and themixture was stirred for 1 h before again being evaporated to dryness.The residue was taken up in DMSO (2 mL) and the mixture was purified byprep LC (Method F, TFA as modifier) to afford the title compound (as TFAsalt) as a white solid (0.028 g, 0.053 mmol, 70% yield). LC-MS (MethodH): 1.31 min, [M+H]⁺=529.2; ¹H NMR (DMSO-d6) δ ppm 13.08 (s, 1H), 12.43(br s, 1H), 8.53 (s, 0.5H) 8.40-8.45 (m, 0.5H), 8.00-8.05 (m, 1H), 7.93(dt, J=7.8, 2.2 Hz, 1H), 7.68-7.90 (m, 5H), 7.49-7.58 (m, 2H), 7.42-7.49(m, 1H), 4.76 (s, 1H), 4.62 (d, J=16.0 Hz, 0.5H), 4.51 (d, J=16.0 Hz,0.5H), 4.39 (d, J=9.8 Hz, 0.5H), 4.14 (d, J=10.6 Hz, 0.5H), 2.43-2.58(m, 1H), 2.07-2.36 (m, 2H), 1.50-1.63 (m, 1H), 1.39-1.49 (m, 1H),1.26-1.38 (m, 1H), 1.15-1.24 (m, 1H), 0.71-0.98 (m, 9H).

Example 435:(S)-3-Methyl-2-(N-((5′-phenoxy-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)butanoicacid

Intermediate 435a: (S)-Methyl2-(N-(4-bromobenzyl)pentanamido)-3-methylbutanoate

The title compound was prepared from (S)-methyl2-amino-3-methylbutanoate hydrochloride, according to the methoddescribed for the synthesis of Intermediate 268b, and was isolated as apale brown oil. LC-MS (Method H): 1.36 min, [M+H]⁺=384.1; ¹H NMR(DMSO-d₆) δ ppm 7.41-7.55 (m, 2H), 7.01-7.18 (m, 2H), 4.47-4.74 (m, 2H),4.11-4.26 (m, 1H), 3.35-3.42 (m, 3H), 2.41-2.60 (m, 1H), 2.05-2.36 (m,2H), 1.13-1.59 (m, 5H), 0.68-0.97 (m, 9H).

Intermediate 435b: (S)-Methyl2-(N-((2′-cyano-5′-fluoro-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate

The title compound was prepared by the reaction of (S)-methyl2-(N-(4-bromobenzyl)pentan-amido)-3-methylbutanoate (0.700 g, 1.82 mmol)with4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(0.900 g, 3.64 mmol), according to the method described for thesynthesis of Intermediate 330b, to give a white solid (0.665 g, 1.57mmol, 86% yield). LC-MS (Method H): 1.38 min, [M+H]⁺=425.2; ¹H NMR(CDCl₃) δ ppm 7.77 (ddd, J=11.0, 8.6, 5.5 Hz, 1H), 7.54 (d, J=8.2 Hz,1H), 7.46 (d, J=8.2 Hz, 1H), 7.28-7.36 (m, 2H), 7.08-7.25 (m, 2H),4.94-5.13 (m, 1H), 4.07-4.29 (m, 1H), 3.39-3.47 (s, 3H), 2.55-2.68 (m,1H), 2.22-2.52 (m, 2H), 1.23-1.83 (m, 5H), 0.79-1.05 (m, 9H).

Intermediate 435c: (S)-Methyl2-(N-((2′-cyano-5′-phenoxy-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate

The title compound was prepared from (S)-methyl2-(N-((2′-cyano-5′-fluoro[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoateand phenol, according to the method described for the synthesis ofIntermediate 330c. The crude product was purified by prep LC (Method F,TFA as modifier) to afford the pure product as a white solid. LC-MS(Method H): 1.48 min, [M+H]⁺=499.2; HRMS (ESI): Calcd for C₃₁H₃₅N₂O₄[M+H]⁺ m/z 499.2591; found 499.2609.

Example 435:(S)-3-Methyl-2-(N-((5′-phenoxy-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)butanoicacid

The title compound was prepared from (S)-methyl2-(N-((2′-cyano-5′-phenoxy-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate,according to the method described for the synthesis of Example 268. Thecrude material was purified by prep LC (Method F, TFA as modifier) toafford the pure product as a white solid. LC-MS (Method H): 1.37 min,[M+H]⁺=528.2; ¹H NMR (DMSO-d₆) δ ppm 7.64 (dd, J=8.4, 5.7 Hz, 1H),7.37-7.53 (m, 2H), 7.06-7.29 (m, 6H), 6.86-7.03 (d, J=2.3 Hz, 3H), 6.94(br s, 1H), 3.90-4.85 (m, 3H), 2.41-2.48 (m, 1H), 1.90-2.30 (m, 2H),1.46-1.71 (m, 1H), 1.41 (br s, 3H), 1.07-1.60 (m, 5H), 0.65-1.05 (m,9H).

The following examples were similarly prepared using the appropriatephenol or hydroxypyridine, according to the method described for thesynthesis of Example 435 above. Analytical LC-MS injections were used todetermine the final purity, the retention time is reported for eachcompound and the method used is referred to as Method A1, Method A2 orMethod H.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 436

528.6 529.2; 1.29 min (Method H) 12.93 (s, 1H), 12.58 (br. s., 1H), 8.53(br. s., 1H), 8.46 (d, J = 4.3 Hz, 1H), 7.60-7.74 (m, 2H), 7.50 (dd, J =8.6, 4.7 Hz, 1H), 7.16- 7.25 (m, 2H), 7.03-7.16 (m, 3H), 6.97 (d, J =7.8 Hz, 1H), 4.53- 4.69 (m, 1H), 4.44 (br. s., 1.5H), 4.07 (d, J = 9.4Hz, 0.5H), 2.39- 2.48 (m, 1H), 1.89-2.27 (m, 2H), 1.07-1.57 (m, 5H),0.66-0.96 (m, 9H) 437

611.1 612.2; 1.45 min (Method H) 12.59 (s, 2H), 7.63-7.74 (m, 1H), 7.57(t, J = 8.4 Hz, 1H), 7.16-7.28 (m, 5H), 7.14 (br. s., 1H), 7.01- 7.12(m, 2H), 6.97 (d, J = 7.8 Hz, 1H), 4.61 (br. s., 1H), 4.45 (d, J = 9.8Hz, 1.5H), 4.07 (d, J = 9.0 Hz, 0.5H), 2.37-2.48 (m, 1H), 1.85- 2.28 (m,2H), 1.07-1.62 (m, 5H), 0.63-0.98 (m, 9H)

Example 438:(S)-2-(N-((3″,5″-Difluoro-6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoicacid

Intermediate 438a: (S)-Methyl2-(N-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate

The title compound was prepared by the reaction of (S)-methyl2-(N-(4-bromobenzyl)pentan-amido)-3-methylbutanoate (0.700 g, 1.82 mmol)with 4-chloro-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile (909mg, 3.64 mmol), according to the method described for the synthesis ofIntermediate 330b, to give a white solid (0.384 g, 0.871 mmol, 48%yield). LC-MS (Method H): 1.44 min, [M+H]⁺=441.2; ¹H NMR (CDCl₃) δ ppm7.65-7.74 (m, 1H), 7.36-7.57 (m, 4H), 7.28-7.36 (m, 2H), 4.94-5.13 (m,1H), 4.29 (d, J=15.7 Hz, 0.5H), 4.07 (d, J=11.0 Hz, 0.5H), 3.47 (s, 2H),3.39 (s, 1H), 2.54-2.70 (m, 1H), 2.22-2.52 (m, 2H), 1.59-1.82 (m, 2H),1.21-1.51 (m, 3H), 0.80-1.04 (m, 9H).

Intermediate 438b: (S)-Methyl2-(N-((6′-cyano-3″,5″-difluoro-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate

The title compound was prepared by the reaction of (S)-methyl2-(N-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoatewith (3,5-difluorophenyl)boronic acid, according to the method describedfor the synthesis of Intermediate 288c, and was isolated as a whitesolid. LC-MS (Method H): 1.48 min, [M+H]⁺=519.2; HRMS (ESI): Calcd forC₃₁H₃₃F₂N₂O₃ [M+H]⁺ m/z 519.2454; found 519.2483.

Example 438:(S)-2-(N-((3″,5″-Difluoro-6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoicacid

The title compound was prepared from (S)-methyl2-(N-((6′-cyano-3″,5″-difluoro-[1,1′:3′,1″-terphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate,according to the method described for the synthesis of Example 268. Thecrude material obtained was purified by prep LC (Method F, TFA asmodifier) to afford the pure product as a white solid. LC-MS (Method H):1.39 min, [M+H]⁺=548.2; ¹H NMR (DMSO-d₆) δ ppm 7.90 (d, J=7.0 Hz, 1H),7.70-7.86 (m, 2H), 7.62 (d, J=7.0 Hz, 2H), 7.08-7.35 (m, 5H), 4.04-4.63(m, 2H), 2.40-2.48 (m, 1H), 2.07-2.21 (m, 2H), 1.12-1.63 (m, 5H),0.69-1.00 (m, 9H).

The following examples have been similarly prepared from thecorresponding boronic acids or boronate esters according to the methodsdescribed for the synthesis of Example 438 above. Analytical LC-MSinjections were used to determine the final purity, the retention timeis reported for each compound and the method used is referred to asMethod A1, Method A2 or Method H.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 439

542.6 543.3; 1.32 min (Method H) 8.23 (dd, J = 4.9, 1.4 Hz, 1H), 7.92(br s, 1H), 7.55-7.77 (m, 3H), 7.04-7.21 (m, 5H), 4.63 (br s, 1H), 4.47(d, J = 9.0 Hz, 1H), 3.91 (s, 3H), 2.46 (m, 1H), 1.91-2.25 (m, 2H),1.10-1.58 (m, 5H), 0.72- 0.97 (m, 9H). 440

568.7 569.3; 1.28 min (Method H) 12.59 (s, 2H), 10.09 (s, 1H), 7.62-7.89 (m, 7H), 6.96-7.22 (m, 4H), 4.40-4.70 (m, 1H), 4.00-4.20 (m, 1H),2.45-2.50 (m, 1H), 2.00- 2.25 (m, 2H), 2.07 (s, 3H), 1.13- 1.60 (m, 5H),0.68-0.98 (m, 9H). 441

562.7 563.2; 1.33 min (Method H) 8.93 (dd, J = 4.3, 1.6 Hz, 1H), 8.46(d, J = 9.0 Hz, 2H), 8.24 (d, J = 7.4 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H),8.00 (d, J = 7.8 Hz, 1H), 7.92 (br s, 1H), 7.80 (dd, J = 7.8, 5.5 Hz,1H), 7.59 (dd, J = 8.2, 4.3 Hz, 1H), 7.11-7.29 (m, 4H), 4.40- 4.75 (m,1H), 3.90-4.25 (m, 1H), 2.45-2.50 (m, 1H), 2.00-2.30 (m, 2H), 1.10-1.60(m, 5H), 0.70- 1.00 (m, 9H). 442

515.6 516.2; 1.26 min. (Method H) 13.01 (br s, 1H), 12.61 (br s, 1H),8.35 (s, 1H), 8.03 (s, 1H), 7.66- 7.79 (m, 2H), 7.55-7.66 (m, 1H), 7.22(d, J = 8.2 Hz, 1H), 7.07- 7.17 (m, 2H), 6.98-7.07 (m, 1H), 4.55-4.66(m, 1H), 4.36-4.55 (m, 1H), 3.88 (s, 3H), 2.45-2.50 (m, 1H), 1.98-2.28(m, 2H), 1.13- 1.55 (m, 5H), 0.65-0.99 (m, 9H).

Example 443:(S)-3-Methyl-2-(N-((5′-(pyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)butanoic

Intermediate 443a: (S)-Methyl2-(N-((2′-cyano-5′-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate

The title compound was prepared by the reaction of (S)-methyl2-(N-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate(Intermediate 438a) with5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane), according to themethod described for the synthesis of Intermediate 293a. The unpurifiedproduct was used as such in the next step. LC-MS (Method H): 1.33 min,[M+H]⁺=no ion observed; ¹H NMR (CDCl₃) δ ppm 7.87-7.93 (m, 1H),7.78-7.87 (m, 1H), 7.67-7.76 (m, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.47 (d,J=8.2 Hz, 1H), 7.24-7.33 (m, 2H), 4.91-5.12 (m, 1H), 4.26 (d, J=15.3 Hz,0.5H), 4.05 (d, J=15.3 Hz, 0.5H) 3.76-3.82 (m, 3H), 3.57-3.63 (s, 4H),2.61 (dd, J=14.7, 8.0 Hz, 1H), 2.23-2.51 (m, 2H), 1.62-1.82 (m, 2H),1.38-1.52 (m, 1H), 1.21-1.37 (m, 2H), 0.83-1.02 (m, 15H)

Intermediate 443b: (S)-Methyl2-(N-((2′-cyano-5′-(pyridin-2-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate

The title compound was prepared by the reaction of (S)-methyl2-(N-((2′-cyano-5′-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate

(Intermediate 443a) with 2-bromopyridine, according to the methoddescribed for the synthesis of Intermediate 293b. The crude materialobtained was purified with prep LC (Method F, formic acid as modifier)to afford the pure product as a white solid. LC-MS (Method H): 1.38 min,[M+H]⁺=484.3; HRMS (ESI): Calcd for C₃₀H₃₄N₃O₃ [M+H]⁺ m/z 484.2595;found 484.2635.

Example 443:(S)-3-Methyl-2-(N-((5′-(pyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)butanoic

The title compound was prepared by the reaction of (S)-methyl2-(N-((2′-cyano-5′-(pyridin-2-yl)-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate(Intermediate 443b) according to the method described for the synthesisof Example 268. The crude material obtained was purified by prep LC(Method F, TFA as modifier) to afford the product (TFA salt) as a whitesolid. LC-MS (Method H): 1.30 min, [M+H]⁺=513.2; ¹H NMR (DMSO-d₆) δ ppm12.96 (s, 1H), 12.59 (s, 1H), 8.71 (d, J=3.9 Hz, 1H), 8.18-8.28 (m, 2H),8.15 (d, J=7.8 Hz, 1H), 7.91-7.97 (m, 1H), 7.73-7.80 (m, 1H), 7.41-7.46(m, 1H), 7.22 (d, J=8.2 Hz, 1H), 7.08-7.17 (m, 2H), 7.02-7.08 (m, 1H),4.63 (s, 1H), 4.44-4.49 (m, 1H), 2.46 (m, 1H), 2.05-2.28 (m, 2H),1.10-1.54 (m, 5H), 0.65-0.95 (m, 9H).

The following examples have been similarly prepared from thecorresponding 2-bromo- or 2-chloropyridines according to the methodsdescribed for the synthesis of Example 443 above. Analytical LC-MSinjections were used to determine the final purity, the retention timeis reported for each compound and the method used is referred to asMethod A1, Method A2 or Method H.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 444

526.6 527.2; 1.32 min (Method H) 12.99 (s, 1H), 12.61 (s, 1H), 8.21-8.26 (m, 1H), 8.19 (d, J = 5.5 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.84(t, J = 7.6 Hz, 1H), 7.73-7.80 (m, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.23(d, J = 7.8 Hz, 1H), 7.10-7.18 (m, 2H), 7.04-7.08 (m, 1H), 4.64 (s, 1H),4.45-4.51 (m, 1H), 2.56 (s, 3H), 2.39-2.48 (m, 1H), 1.97- 2.29 (m, 2H),1.12-1.64 (m, 5H), 0.66-0.99 (m, 9H). 445

526.6 527.2; 1.31 min (Method H) 12.97 (s, 1H), 12.58 (s, 1H), 8.57 (d,J = 5.1 Hz, 1H), 8.21-8.26 (m, 1H), 8.16-8.21 (m, 1H), 8.05 (s, 1H),7.74-7.80 (m, 1H), 7.31 (d, J = 4.7 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H),7.09-7.17 (m, 2H), 7.03- 7.08 (m, 1H), 4.63 (s, 1H), 4.43- 4.49 (m, 1H),2.39-2.46 (m, 3H), 1.98-2.28 (m, 2H), 1.10-1.58 (m, 5H), 0.63-0.97 (m,9H). 446

542.6 543.2; 1.38 min (Method H) 8.22 (dd, J = 7.8, 1.6 Hz, 1H), 8.15(s, 1H), 7.78-7.85 (m, 1H), 7.67- 7.77 (m, 2H), 7.25 (d, J = 7.4 Hz,1H), 7.09-7.16 (m, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.84 (d, J = 8.2 Hz,1H), 4.71 (br s, 1H), 4.54 (br s, 1H), 3.94 (s, 3H), 2.40-2.50 (m, 1H),1.94-2.30 (m, 2H), 1.10- 1.60 (m, 5H), 0.60-1.00 (m, 9H).

The following examples have been similarly prepared from (S)-methyl2-(N-((5′-chloro-2′-cyano-[1,1′-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoate(Intermediate 438a) together with the appropriate amine, according tothe method described for the synthesis of Example 297. Analytical LC-MSinjections were used to determine the final purity, the retention timeis reported for each compound and the method used is referred as MethodA1, Method A2 or Method H.

LC-MS m/z [M + H]⁺; RT ¹H NMR (400 MHz, DMSO-d₆) Ex Structure MW(Method) δ ppm 447

532.7 533.3; 1.40 min (Method H) 12.58 (s, 2H), 7.37-7.46 (m, 1H), 7.16(d, J = 8.2 Hz, 1H), 7.06 (d, J = 8.2 Hz, 3H), 6.96 (d, J = 8.2 Hz, 1H),6.88 (d, J = 2.7 Hz, 1H), 4.53-4.67 (m, 1H), 4.38-4.50 (m, 1H), 3.86 (d,J = 12.5 Hz, 2H), 2.78 (t, J = 12.3 Hz, 2H), 2.36- 2.46 (m, 1H),1.96-2.26 (m, 2H), 1.68 (d, J = 11.7 Hz, 2H), 1.10- 1.62 (m, 8H),0.63-0.98 (m, 12H). 448

532.7 533.2; 1.41 min (Method H) 12.60 (br s, 2H), 7.38-7.45 (m, 1H),7.17 (d, J = 7.8 Hz, 1H), 7.01- 7.09 (m, 3H), 6.96 (d, J = 7.8 Hz, 1H),6.88 (d, J = 2.3 Hz, 1H), 4.53-4.68 (m, 1H), 4.36-4.50 (m, 1H),3.71-3.87 (m, 2H), 2.74 (t, J = 12.1 Hz, 1H), 2.37-2.46 (m, 2H),1.97-2.26 (m, 2H), 1.24- 1.80 (m, 8H), 1.01-1.20 (m, 2H), 0.60-0.98 (m,12H). 449

526.6 527.2; 1.33 min (Method H) 12.57 (s, 2H), 8.59-8.68 (m, 1H),7.40-7.50 (m, 1H), 7.25-7.35 (m, 2H), 7.10-7.23 (m, 4H), 7.01- 7.10 (m,3H), 6.88-6.99 (m, 2H), 4.60 (s, 1H), 4.35-4.52 (m, 1H), 2.37-2.46 (m,1H), 1.96- 2.25 (m, 2H), 1.03-1.60 (m, 5H), 0.61-0.96 (m, 9H). 450

580.2 581.3; 1.48 min. (Method H) 7.58 (t, J = 7.6 Hz, 1H), 7.39 (d, J =8.2 Hz, 1H), 6.96-7.32 (m, 8H), 6.83 (t, J = 7.4 Hz, 1H), 4.55- 4.68 (m,1H), 4.46 (d, J = 9.8 Hz, 1H), 2.38-2.46 (m, 1H), 1.93- 2.19 (m, 2H),1.03-1.56 (m, 11H), 0.65-0.98 (m, 9H).

Example 451:3-((6-(4-(2H-Tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 451a:3-((6-Bromopyridin-3-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

To a solution of 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one.HCl (0.218 g,0.918 mmol) in DMF (3 mL) at 30-35° C. was added freshly pulverized NaOH(0.084 g, 2.112 mmol). The resulting mixture was stirred at the sametemperature under N₂ for 30 min. Then a solution of2-bromo-5-(bromomethyl)pyridine (0.240 g, 0.918 mmol) in DMF (2 mL) wasadded dropwise and the reaction mixture was stirred at the sametemperature for 16 h. The mixture was then cooled at 0° C. and H₂O (12mL) was added dropwise. The cooling bath was then removed and theresulting mixture was stirred at RT for 30 min, after which theresulting slurry was filtered and the filter-cake washed with H₂O. Thewet filter-cake was partitioned with DCM-saturated aqueous Na₂CO₃ andthe organic phase was separated, dried (Na₂SO₄) and evaporated to give anearly colourless gum. This material was triturated with hexane to givea crystalline solid, which was filtered and washed with a little morehexane. After drying in vacuo, this gave the pure product (191 mg, 57%)as an off-white solid. The filtrate was evaporated and the residue wasagain triturated with a minimum volume of hexane. The supernatant wasdecanted and the residue was dried in vacuo to give another 45 mg (13%)of the pure product as a white crystalline solid. These solids werecombined to give pure3-((6-bromopyridin-3-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one(0.236 g, 70.6% yield), which was used as such in the next step. LC-MS(Method H): 1.265 min, [M+H]⁺=364.0. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.25 (d, J=2.7 Hz, 1H), 7.63 (d, J=8.2 Hz, 1H), 7.50 (dd, J=2.7, 8.2 Hz,1H), 4.68 (s, 2H), 2.34 (t, J=7.4 Hz, 2H), 1.81 (m, 6H), 1.63 (m, 2H),1.46 (quint, J=7.4 Hz, 2H), 1.26 (m, 2H), 0.80 (t, J=7.4 Hz, 3H).

Intermediate 451b:3-(5-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)pyridin-2-yl)-[1,1′-biphenyl]-4-carbonitrile

The title compound was prepared by the reaction of3-((6-bromopyridin-3-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one(Intermediate 451a, 0.044 g, 0.121 mmol) with3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-4-carbonitrile(Intermediate 268c, 0.042 g, 0.145 mmol), according to the methoddescribed for the synthesis of Intermediate 330b, to give a white solid(0.062 g, 111%). This material was contaminated with residual Ph₃PO, butwas sufficiently pure to be used as such in the next step. LC-MS (MethodH): 1.34 min, [M+H]⁺=463.2; ¹H NMR (DMSO-d₆) δ ppm 8.63 (d, J=2.0 Hz,1H), 8.13 (d, J=2.0 Hz, 1H), 8.05 (d, J=8.2 Hz, 1H), 8.02 (d, J=7.8 Hz,1H), 7.91-7.98 (m, 1H), 7.81-7.89 (m, 2H), 7.75 (dd, J=8.2, 2.3 Hz, 1H),7.50-7.56 (m, 2H), 7.44-7.50 (m, 1H), 4.31 (t, J=5.5 Hz, 2H), 2.42 (t,J=7.4 Hz, 2H), 1.77-1.96 (m, 6H), 1.61-1.77 (m, 2H), 1.52 (dt, J=15.1,7.3 Hz, 2H), 1.19-1.36 (m, 2H), 0.82 (t, J=7.4 Hz, 3H).

Example 451:3-((6-(4-(1H-Tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)pyridin-3-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

The title compound was prepared by the reaction of3-(5-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)pyridin-2-yl)-[1,1′-biphenyl]-4-carbonitrile(Intermediate 451b, 0.055 g, 0.119 mmol), according to the methoddescribed for the synthesis of Intermediate 283a, to give a white solid(0.047 g, 78%). LC-MS (Method H): 1.28 min, [M+H]⁺=506.1; ¹H NMR(DMSO-d₆) δ ppm 8.38 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.95(dd, J=8.2, 2.0 Hz, 1H), 7.77-7.87 (m, 3H), 7.72 (dd, J=8.2, 2.3 Hz,1H), 7.63 (d, J=8.2 Hz, 1H), 7.49-7.56 (m, 2H), 7.39-7.49 (m, 1H), 4.89(s, 2H), 2.66 (t, J=7.2 Hz, 2H), 1.77-2.04 (m, 8H), 1.43-1.62 (m, 2H),1.23-1.40 (m, 2H), 0.79-0.92 (m, 3H).

Example 452:3-((5-Bromopyridin-2-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 452a:3-((5-Bromopyridin-2-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

The title compound was prepared by the reaction of2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one.HCl (0.250 g, 1.083 mmol) with5-bromo-2-(chloromethyl)pyridine.HCl (0.263 g, 1.083 mmol), according tothe method described for the synthesis of Intermediate 451a, to give awhite solid (0.300 g, 76%). LC-MS (Method H): 1.23 min, [M+H]⁺=364.0; ¹HNMR (DMSO-d₆) δ ppm 8.63 (dd, J=2.3, 0.8 Hz, 1H), 8.04 (dd, J=8.2, 2.3Hz, 1H), 7.24 (d, J=8.2 Hz, 1H), 4.75 (s, 2H), 2.25-2.41 (m, 2H),1.71-1.94 (m, 6H), 1.56-1.71 (m, 2H), 1.43-1.56 (m, 2H), 1.27 (dq,J=15.0, 7.4 Hz, 2H), 0.81 (t, J=7.2 Hz, 3H).

Intermediate 452b:3-(6-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)pyridin-3-yl)-[1,1′-biphenyl]-4-carbonitrile

The title compound was prepared by the reaction of3-((5-bromopyridin-2-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one(Intermediate 452a, 0.100 g, 0.275 mmol) with3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-4-carbonitrile(Intermediate 268c, 0.096 g, 0.329 mmol), according to the methoddescribed for the synthesis of Intermediate 330b, to give a white solid(0.121 g, 95%) which was used as such in the next step. LC-MS (MethodH): 1.39 min, [M+H]⁺=463.1; ¹H NMR (DMSO-d₆) δ ppm 8.83 (d, J=2.0 Hz,1H), 8.15 (dd, J=8.2, 2.3 Hz, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.97 (d,J=1.6 Hz, 1H), 7.94 (dd, J=8.2, 2.0 Hz, 1H), 7.80-7.90 (m, 2H),7.39-7.57 (m, 4H), 4.88 (s, 2H), 2.42 (t, J=7.6 Hz, 2H), 1.76-1.96 (m,6H), 1.61-1.76 (m, 2H), 1.54 (quint, J=7.5 Hz, 2H), 1.19-1.37 (m, 2H),0.83 (t, J=7.4 Hz, 3H).

Example 452:3-((5-(4-(2H-Tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)pyridin-2-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one

The title compound was prepared by the reaction of3-(6-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)pyridin-3-yl)-[1,1′-biphenyl]-4-carbonitrile(Intermediate 452b, 0.055, 0.119 mmol), according to the methoddescribed for the synthesis of Intermediate 283a, to give a white solid(0.055 g, 91%). LC-MS (Method H): 1.33 min, [M+H]⁺=506.2; ¹H NMR(DMSO-d₆) δ ppm 8.39 (d, J=2.0 Hz, 1H), 7.93-7.98 (m, 1H), 7.81-7.90 (m,4H), 7.68 (dd, J=8.0, 2.2 Hz, 1H), 7.48-7.57 (m, 2H), 7.41-7.48 (m, 1H),7.38 (d, J=8.2 Hz, 1H), 5.03 (s, 2H), 2.70 (t, J=6.8 Hz, 2H), 1.75-2.05(m, 8H), 1.58 (dt, J=15.2, 7.5 Hz, 2H), 1.32 (dq, J=14.9, 7.4 Hz, 2H),0.85 (t, J=7.4 Hz, 3H).

Example 453:3-(3-(6-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)pyridin-3-yl)-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5(4H)-one

Intermediate 453a:(Z)-3-(6-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)pyridin-3-yl)-N′-hydroxy-[1,1′-biphenyl]-4-carboximidamide

The title compound was prepared by the reaction of3-(6-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)pyridin-3-yl)-[1,1′-biphenyl]-4-carbonitrile(Intermediate 452b, 0.060 g, 0.130 mmol) with hydroxylaminehydrochloride, according to the method described for the synthesis ofIntermediate 280a, to give a white solid (0.011 g, 17.1%) which was usedas such in the next step. LC-MS (Method H): 1.32 min, [M+H]⁺=496.2; HRMS(ESI): Calcd for C₃₀H₃₄N₅O₂ [M+H]⁺ m/z 496.2702; found 496.2720.

Example 453:3-(3-(6-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)pyridin-3-yl)-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-5(4H)-one

The title compound was prepared by the reaction of(Z)-3-(6-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)pyridin-3-yl)-N′-hydroxy-[1,1′-biphenyl]-4-carboximidamide(Intermediate 453a, 0.011 g, 0.022 mmol), according to the methoddescribed for the synthesis of Example 280, to give a white solid (0.006g, 51.8%). LC-MS (Method H): 1.36 min, [M+H]⁺=522.2; ¹H NMR (DMSO-d₆) δppm 12.63 (br s, 1H), 8.57 (d, J=2.0 Hz, 1H), 7.91-7.97 (m, 1H),7.86-7.91 (m, 1H), 7.80-7.86 (m, 4H), 7.42-7.57 (m, 4H), 5.05 (s, 2H),2.61-2.78 (m, 2H), 1.76-2.03 (m, 8H), 1.58 (dt, J=15.3, 7.6 Hz, 2H),1.32 (dq, J=15.0, 7.4 Hz, 2H), 0.85 (t, J=7.4 Hz, 3H).

Example 454:2-Butyl-3-((5′-phenoxy-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 454a:2-Butyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one

To a suspension of sodium hydride (60% in oil, 0.150 g, 3.75 mmol) inDMF (7.5 mL) was added 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one.HCl(0.357 g, 1.500 mmol) all at once and the mixture was stirred at RTunder N₂ for 30 min. To this mixture was added a solution of2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.535g, 1.800 mmol) in DMF (2.5 mL) dropwise and stirring was continued atthe RT for 1 h. The volatiles were then removed under reduced pressureto give a milky white gum that was taken up in a minimum volume of DCMand applied to a silica gel pre-column Flash chromatography (ISCO/0-100%EtOAc-hexane) afforded2-butyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one(0.477 g, 77% yield) as a clear, colourless gum. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.63 (d, J=7.8 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 4.68 (s,2H), 2.26 (t, J=7.4 Hz, 2H), 1.82 (m, 6H), 1.64 (m, 2H), 1.43 (quint,J=7.4 Hz, 2H), 1.26 (s, 12H), 1.22 (m, 2H), 0.76 (t, J=7.4 Hz, 3H).

Intermediate 454b:4′-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carbonitrile

A mixture of2-butyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one(0.060 g, 0.146 mmol), 2-bromo-4-phenoxybenzonitrile (Intermediate 204a,0.050 g, 0.183 mmol) and 2 M Na₂CO₃ (0.183 mL, 0.383 mmol) intoluene-ethanol (9:1, 5 mL) was purged with a stream of N₂ for 5 min ina sealable vial. To this mixture was added Pd (Ph₃P)₄ (0.017 g, 0.015mmol), the vial was sealed and the mixture was stirred at 95° C. (blocktemperature) for 16 h. The cooled mixture was diluted with EtOAc and theorganic phase was separated, dried (Na₂SO₄) and evaporated to give aclear gum. This material was purified by flash chromatography(ISCO/0-100% EtOAc-DCM) to give4′-((2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carbonitrile(0.039 g, 55.8% yield) as a colourless gum. This gum was lyophilizedfrom ACN-H₂O to give a white solid which was used as such in the nextstep. LC-MS (Method H): 1.482 min, [M+H]⁺=478.1; ¹H NMR (400 MHz,DMSO-d₆) δ ppm 7.92 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.46 (t,J=8.0 Hz, 2H), 7.28-7.24 (m, 3H), 7.18 (d, J=8.2 Hz, 2H), 7.09 (d, J=2.3Hz, 1H), 7.05 (dd, J=2.7, 8.6 Hz, 1H), 4.74 (s, 2H), 2.32 (t, J=7.4 Hz,2H), 1.83 (m, 6H), 1.66 (m, 2H), 1.45 (quint, J=7.4 Hz, 2H), 1.23 (m,2H), 0.75 (t, J=7.4 Hz, 3H).

Example 454:2-Butyl-3-((5′-phenoxy-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

To a mixture of4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-phenoxy-[1,1′-biphenyl]-2-carbonitrile(0.015 g, 0.031 mmol), TMS-N₃ (0.044 mL, 0.314 mmol) and dibutyltinoxide (0.016 g, 0.063 mmol) in a 4 mL vial was added toluene (2 mL). Thevial was briefly purged with N₂ and then it was sealed and the mixturewas stirred at 120° C. (block temperature) for 16 h. The cooled mixturewas evaporated and the residual gum was taken up in DMF (acidified witha 10 drops of AcOH) and filtered using a 0.45 pin syringe filter. Thefiltrate was submitted to prep LC purification (Method D) and theproduct-containing fractions were combined and evaporated to give a gum.This material was lyophilized from ACN-H₂O to give2-butyl-3-((5′-phenoxy-2′-(1H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one(0.009 g, 55.0% yield) as a white solid. LC-MS (Method H): 1.388 min,[M+H]⁺=521.1; HRMS (ESI): Calcd. for C₃₁H₃₃N₆O₂ [M+H]⁺ m/z 521.2665;found 521.2672. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.65 (d, J=8.6 Hz, 1H),7.44 (t, J=8.0 Hz, 2H), 7.21 (t, J=7.4 Hz, 1H), 7.16 (d, J=7.8 Hz, 2H),7.12 (dd, J=2.3, 8.2 Hz, 1H), 7.05 (s, 5H), 4.64 (s, 2H), 2.25 (t, J=7.4Hz, 2H), 1.81 (m, 6H), 1.63 (m, 2H), 1.43 (quint, J=7.4 Hz, 2H), 1.22(m, 2H), 0.75 (t, J=7.4 Hz, 3H).

Example 455:2-Butyl-3-((5′-((4-methylpyridin-2-yl)oxy)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

Intermediate 455a:4′-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-hydroxy-[1,1′-biphenyl]-2-carbonitrile

In a 15-mL vial, a stream of Ar was passed through a mixture of2-butyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one(Intermediate 454a, 0.259 g, 0.63 mmol), 2-bromo-4-hydroxybenzonitrile(0.15 g, 0.76 mmol) and 2M Na₂CO₃ (0.95 mL, 1.9 mmol) in a mixture oftoluene (3 mL) and ethanol (0.3 mL) for 5 min. To this mixture was addedPd (PPh₃)₄ (0.036 g, 0.032 mmol) and Ar was again bubbled through themixture for an additional 5 min. The vial was then sealed and themixture was heated at 95° C. for 12 h. The mixture was allowed to coolto RT and saturated aqueous ammonium chloride (20 mL) and EtOAc (20 mL)were added. The organic phase was separated and the aqueous layer wasre-extracted with EtOAc (2×20 mL). The combined organic extract waswashed with brine, dried (anhydrous MgSO₄), filtered and evaporated. Theresidue obtained was purified using a 12 g RediSep column on an ISCOinstrument eluting with 0-100% EtOAc-DCM to afford the title compound(0.070 g, 27.7% yield). LC-MS (Method H): 1.25 min, [M+H]⁺=402.2.

Intermediate 455b:4′-((2-Butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-((4-methylpyridin-2-yl)oxy)-[1,1′-biphenyl]-2-carbonitrile

In a conical 2-mL vial, a stream of Ar was passed through a suspensionof4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-hydroxy-[1,1′-biphenyl]-2-carbonitrile(0.038 g, 0.095 mmol), 2-chloro-4-methylpyridine (0.025 mL, 0.28 mmol)and cesium carbonate (0.093 g, 0.28 mmol) in toluene (0.24 mL). After 5min, palladacycle precatalyst J009 PreCat (0.0015 g, 1.6 μmol) was addedand Ar was bubbled through the mixture for an additional 5 min. The vialwas then sealed and heated at 100° C. for 24 h. The mixture was thenallowed to cool to RT, saturated aqueous ammonium chloride (5 mL) andEtOAc (10 mL) were added and the separated aqueous layer was extractedwith EtOAc (2×10 mL). The combined organic extract was washed withbrine, dried (anhydrous MgSO₄), filtered and evaporated. The residueobtained was purified using a 24 g RediSep column on an ISCO instrumenteluting with 0-100% EtOAc-DCM to afford4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-((4-methylpyridin-2-yl)oxy)-[1,1′-biphenyl]-2-carbonitrile(0.026 g, 55.8% yield). LC-MS (Method H): 1.33 min, [M+H]⁺=493.2. HRMS(ESI): Calcd for C₃₁H₃₃N₄O₂ [M+H]⁺ m/z 493.2598; found: 493.2580.

Example 455:2-Butyl-3-((5′-((4-methylpyridin-2-yl)oxy)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one

In a conical 2-mL vial was added4′-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-5-((4-methylpyridin-2-yl)oxy)-[1,1′-biphenyl]-2-carbonitrile(0.026 g, 0.053 mmol), dibutyltin oxide (0.014 g, 0.058 mmol) and TMS-N₃(0.056 mL, 0.42 mmol) in toluene (0.3 mL) and the sealed vial was heatedat 100° C. for 12 h. The mixture was then allowed to cool to RT and thevolatiles were removed under reduced pressure. The residue was dissolvedin DMSO and the mixture was filtered (0.46 μm syringe filter) and thefiltrate purified by preparative HPLC (Method D) to afford2-butyl-3-((5′-((4-methylpyridin-2-yl)oxy)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-1,3-diazaspiro[4.4]non-1-en-4-one(0.014 g, 50.2%) as a solid. LC-MS (Method H): 1.28 min, [M+H]⁺=536.2.¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.05 (d, J=5.1 Hz, 1H), 7.69 (d, J=8.6Hz, 1H), 7.30 (dd, J=8.6, 2.4 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 7.08 (m,4H), 7.01 (m, 2H), 4.66 (s, 2H), 2.36 (s, 3H), 2.27 (t, J=7.4 Hz, 2H),1.84 (m, 6H), 1.64 (m, 2H), 1.45 (q, J=7.4 Hz, 2H), 1.24 (m, 2H), 0.78(t, J=7.2 Hz, 3H).

Example 456:5-(4″-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2H-tetrazole

Intermediate 456a: 1-(4-Bromobenzyl)-3,5-dimethyl-1H-1,2,4-triazole

In a 50 mL round-bottomed flask under N₂ at 0° C., sodium hydride (60%in mineral oil, 0.184 g, 4.60 mmol) was added to a solution of3,5-dimethyl-1H-1,2,4-triazole (0.311 g, 3.20 mmol) in DMF (12 mL) andthe mixture was stirred for 20 min 4-Bromobenzyl bromide (0.960 g, 3.84mmol) was then added to the mixture and stirring was continued at RT for2.5 h. The reaction mixture was then poured into H₂O and the product wasextracted with EtOAc (×3). The combined organic extract was washed withH₂O (×3) and brine, dried over anhydrous sodium sulfate and concentratedto dryness. The residue was purified on ISCO using a 40 g column (0-20%MeOH-DCM) to afford the title compound (0.382 g, 1.44 mmol, 45% yield)as an off-white solid. LC (Method B): 1.538 min MS (APCI): calcd forC₁₁H₁₃BrN₃+m/z 266.0, found 266.1. ¹H NMR (400 MHz, CDCl₃) δ ppm7.43-7.52 (m, 2H), 7.00-7.08 (m, J=8.22 Hz, 2H), 5.16 (s, 2H), 2.37 (s,3H), 2.35 (s, 3H).

Intermediate 456b:4″-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

In a 5 mL sealable vial, a solution of1-(4-bromobenzyl)-3,5-dimethyl-1H-1,2,4-triazole (0.059 g, 0.22 mmol)and3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-[1,1′-biphenyl]-4-carbonitrile(Intermediate 268c, 0.078 g, 0.27 mmol) in a mixture of ethanol (0.2 mL)and toluene (1.8 mL) was purged with a stream of N₂ for 10 min.Tetrakis(triphenylphosphine) palladium (0) (0.026 g, 0.022 mmol) and 2Maqueous Na₂CO₃ (0.33 mL, 0.66 mmol) were added, the vial was sealed andthe mixture was stirred at 100° C. for 1.75 h. After being stored at RTfor 16 h, the mixture was diluted in EtOAc and filtered over Celite®.The filtrate was then concentrated to dryness and the residue waspurified on ISCO using a 12 g column (0-5% MeOH-DCM) to afford the titlecompound (0.096 g, 0.18 mmol, 70% purity, 83% yield), contaminated withtriphenylphosphine oxide, as a white solid. LC (Method B): 1.985 min MS(APCI): calcd for C₂₄H₂₁N₄+m/z 365.2, found 365.2. ¹H NMR (400 MHz,CDCl₃) δ ppm 7.84 (d, J=7.83 Hz, 1H), 7.65-7.71 (m, 3H), 7.59-7.65 (m,3H), 7.45-7.51 (m, 3H), 7.31 (d, J=8.22 Hz, 2H), 5.30 (s, 2H), 2.43 (s,3H), 2.38 (s, 3H).

Example 456:5-(4″-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-yl)-2H-tetrazole

In a vial under N₂, a mixture of4″-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile(0.040 g, 0.077 mmol), dibutyltin oxide (0.034 g, 0.14 mmol) and TMS-N₃(0.180 mL, 1.36 mmol) in toluene (3 mL) was stirred at 120° C. for 16.5h. The cooled reaction mixture was poured into MeOH and the resultingmixture was concentrated to dryness. The crude residue was dissolved inDMF and purified twice by reverse-phase preparative LC (Method D) andthe product was lyophilized from ACN-H₂O to afford the title compound(0.019 mg, 0.046 mmol, 60% yield) as a white solid. LC (Method B): 1.838min MS (APCI): calcd for C₂₄H₂₂N₇ [M+H]⁺ m/z 408.2, found 408.1. ¹H NMR(400 MHz, CDCl₃) δ ppm 8.10 (d, J=8.22 Hz, 1H), 7.80 (dd, J=1.76, 8.02Hz, 1H), 7.63-7.72 (m, 3H), 7.47-7.54 (m, 2H), 7.39-7.47 (m, 1H),7.16-7.23 (m, 2H), 6.96-7.05 (m, 2H), 5.19 (s, 2H), 2.27 (s, 3H), 2.08(s, 3H).

Example 457:5-(4′-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-5-(4-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-2-yl)-2H-tetrazole

Intermediate 457a:4′-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile

In a 5 mL sealable vial, a solution of1-(4-bromobenzyl)-3,5-dimethyl-1H-1,2,4-triazole (0.165 g, 0.620 mmol)and 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(0.229 g, 0.927 mmol) in a mixture of ethanol (0.6 mL) and toluene (5.4mL) was purged with a stream of N₂ for 20 minTetrakis(triphenylphosphine) palladium (0) (0.072 g, 0.062 mmol) and 2Maqueous Na₂CO₃ (0.93 mL, 1.860 mmol) were added, the vial was sealed andthe mixture was stirred at 100° C. for 3.5 h. The cooled mixture wasdiluted with EtOAc and the resulting mixture was filtered over Celite®.The filtrate was then concentrated to dryness and the residue waspurified twice on ISCO using a 40 g column (0-5% MeOH-DCM). The materialobtained was dissolved in DMF and repurified by reverse-phasepreparative LC (Method D) and the product obtained was lyophilized fromACN-H₂O to afford the title compound (0.094 g, 0.31 mmol, 50% yield) asa white solid. LC (Method B): 1.617 min MS (APCI): calcd for C₁₈H₁₆FN₄[M+H]⁺ m/z 307.1, found 307.1. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.78 (dd,J=5.67, 8.41 Hz, 1H), 7.52-7.57 (m, 2H), 7.28-7.32 (m, 2H), 7.13-7.22(m, 2H), 5.29 (s, 2H), 2.42 (s, 3H), 2.38 (s, 3H).

Intermediate 457b:4′-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-5-(4-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-2-carbonitrile

In a vial under N₂, a mixture of4′-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-5-fluoro-[1,1′-biphenyl]-2-carbonitrile(0.038 g, 0.12 mmol), 4-methyl-1H-pyrazole (0.020 mL, 0.24 mmol) andpotassium carbonate (0.040 g, 0.29 mmol) in DMF (2 mL) was heated at100° C. for 18 h. Additional 4-methyl-1H-pyrazole (0.020 mL, 0.24 mmol)was added and the mixture was heated at 100° C. for another 3 days. Thecooled mixture was acidified with formic acid (0.050 mL) and thesolution was purified by reverse-phase preparative LC (Method D). Theproduct obtained was lyophilized from ACN-H₂O to afford the titlecompound (0.038 g, 0.10 mmol, 84% yield) as a white solid. LC (MethodB): 1.828 min MS (APCI): calcd for C₂₂H₂₁N₆ [M+H]⁺ m/z 369.2, found369.2. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.77-7.84 (m, 3H), 7.73 (dd,J=2.20, 8.40 Hz, 1H), 7.58-7.63 (m, 3H), 7.28-7.33 (m, 2H), 5.30 (s,2H), 2.43 (s, 3H), 2.38 (s, 3H), 2.18 (s, 3H).

Example 457:5-(4′-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-5-(4-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-2-yl)-2H-tetrazole

In a vial under N₂, a mixture of4′-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-5-(4-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-2-carbonitrile(0.036 g, 0.098 mmol), dibutyltin oxide (0.031 g, 0.13 mmol) and TMS-N₃(0.13 mL, 0.98 mmol) in toluene (3 mL) was stirred at 120° C. for 17 h.The cooled reaction mixture was poured into MeOH and the resultingmixture was concentrated to dryness. The crude material was dissolved inDMF and purified twice by reverse-phase preparative LC (Method D) andthe product obtained was lyophilized from ACN-H₂O to afford the titlecompound (0.027 g, 0.066 mmol, 67% yield) as a white solid. LC (MethodB): 1.632 min MS (APCI): calcd for C₂₂H₂₂N₉ [M+H]⁺ m/z 412.2, found412.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.49 (s, 1H), 7.99 (dd, J=8.4,2.2 Hz, 1H), 7.92 (d, J=2.0 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 7.64 (s,1H), 7.16 (s, 4H), 5.27 (s, 2H), 2.35 (s, 3H), 2.17 (s, 3H), 2.11 (s,3H).

Example 458:2-(4′-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)-4-methylpyridine

Intermediate 458a:5-Bromo-4′-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

In a 25 mL round-bottomed flask under N₂ at 0° C., sodium hydride (60%in mineral oil, 0.059 g, 1.48 mmol) was added to a solution of3,5-dimethyl-1H-1,2,4-triazole (0.112 g, 1.15 mmol) in DMF (5 mL) andthe mixture was stirred for 30 min. To this mixture was then added5-bromo-4′-(bromomethyl)-[1,1′-biphenyl]-2-carbonitrile (I-002, 0.407 g,1.16 mmol) and the mixture was stirred at RT for 3.5 h. The resultingmixture was then poured into H₂O and the product was extracted withEtOAc (×3). The combined organic extract was washed with H₂O (×3) andbrine, dried over anhydrous sodium sulfate and concentrated to dryness.The residue was purified on ISCO using a 40 g column (0-5% MeOH-DCM) toafford the title compound (0.248 mg, 0.675 mmol, 59% yield) as acolorless gum. LC (Method B): 1.795 min MS (APCI): calcd for C₁₈H₁₆BrN₄[M+H]⁺ m/z 367.1, found 367.0. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.66 (dd,J=0.78, 1.57 Hz, 1H), 7.61-7.63 (m, 2H), 7.51-7.56 (m, 2H), 7.28-7.31(m, 2H), 5.29 (s, 2H), 2.42 (s, 3H), 2.38 (s, 3H).

Intermediate 458b:5-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-4′-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

In a 5 mL sealable vial, a mixture of5-bromo-4′-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.079 g, 0.22 mmol) and5,5,5′,5′-tetramethyl-2,2′-bi(1,3,2-dioxaborinane) (0.122 g, 0.540 mmol)in 1,4-dioxane (3 mL) was purged with a stream of N₂ for 10 min. To thismixture was added XPhos Pd G2 (0.030 g, 0.038 mmol), followed by KOAc(0.066 g, 0.67 mmol) and the mixture was heated at 85° C. for 2.75 h.The cooled reaction mixture was poured into H₂O, the product wasextracted with EtOAc (×3) and the combined organic extract was washedwith brine, dried over anhydrous sodium sulfate and concentrated todryness. The residue was purified on ISCO using a 25 g column (0-5%MeOH-DCM) to afford the title compound (0.106 g, 0.169 mmol, 64% purity,79% yield) as a white solid. LC (Method B): 1.534 min MS (APCI): calcdfor C₁₈H₁₈BN₄O₂ [M-C₅H₁₀O₂+2OH]⁺ m/z 333.2, found 333.1. ¹H NMR (400MHz, CDCl₃) δ ppm 7.90 (s, 1H), 7.85 (dd, J=7.6, 1.0 Hz, 1H), 7.73 (d,J=7.8 Hz, 1H), 7.54-7.59 (m, 2H), 7.27 (d, J=8.2 Hz, 2H), 5.28 (s, 2H),3.79 (s, 4H), 2.41 (s, 3H), 2.38 (s, 3H), 1.04 (s, 6H).

Intermediate 458c:4′-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-5-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

In a 5 mL sealable vial, a mixture of5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4′-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.068 g, 0.17 mmol) and 2-bromo-4-methylpyridine (0.060 mL, 0.54 mmol)in DME (2 mL) was purged with a stream of N₂ for 10 min. To this mixturewas added tetrakis(triphenylphosphine) palladium (0) (0.024 g, 0.021mmol) and 2M aqueous Na₂CO₃ (0.35 mL, 0.70 mmol) and the mixture washeated at 85° C. for 17 h. The cooled reaction mixture was concentratedto dryness and the residue was purified on ISCO using a 25 g column(0-10% MeOH-DCM) to afford the title compound (0.064 g, 0.17 mmol, 100%yield) as an off-white solid. LC (Method B): 1.579 min MS (APCI): calcdfor C₂₄H₂₂N₅ m/z 380.2, found 380.2. ¹H NMR (400 MHz, DMSO-d₆) δ ppm8.57 (d, J=5.1 Hz, 1H), 8.25-8.32 (m, 2H), 8.03-8.09 (m, 2H), 7.64-7.69(m, 2H), 7.35-7.41 (m, 2H), 7.29 (d, J=5.1 Hz, 1H), 5.37 (s, 2H), 3.15(s, 3H), 3.13 (s, 3H), 2.19 (s, 3H).

Example 458:2-(4′-((3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl)-6-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-3-yl)-4-methylpyridine

In a vial under N₂, a mixture of4′-((3,5-dimethyl-1H-1,2,4-triazol-1-yl)methyl)-5-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile(0.064 g, 0.17 mmol), dibutyltin oxide (0.052 g, 0.21 mmol) and TMS-N₃(0.23 mL, 1.73 mmol) in toluene (3.5 mL) was stirred at 120° C. for 17h. The cooled reaction mixture was poured into MeOH and the resultingmixture was concentrated to dryness. The crude material was purifiedtwice by reverse-phase preparative LC (Method D) and the productobtained was lyophilized from ACN-H₂O to afford the title compound(0.035 g, 0.082 mmol, 49% yield) as a white solid. LC (Method B): 1.281min MS (APCI): calcd for C₂₄H₂₃N₈ [M+H]⁺ m/z 423.2, found 423.1. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.55 (d, J=4.7 Hz, 1H), 8.27 (dd, J=7.8, 1.6Hz, 1H), 8.19 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.79 (d, J=8.2 Hz, 1H),7.25 (d, J=5.1 Hz, 1H), 7.11-7.21 (m, 4H), 5.27 (s, 2H), 2.41 (s, 3H),2.35 (s, 3H), 2.17 (s, 3H).

Example 459:5-(5-(4-Methyl-1H-pyrazol-1-yl)-4′-((3-methyl-4H-1,2,4-triazol-4-yl)methyl)-[1,1′-biphenyl]-2-yl)-2H-tetrazole

Intermediate 459a: 4-(4-Bromobenzyl)-3-methyl-4H-1,2,4-triazole

In a 100 mL round-bottomed flask equipped with a condenser, a mixture oftriethyl orthoformate (0.5 mL, 3.01 mmol), acetohydrazide (0.219 g, 2.96mmol) and DBU (0.33 mL, 2.19 mmol) in xylene (10 mL) was heated atreflux under N₂ for 1.5 h. The reaction mixture was allowed to cool toRT and then (4-bromophenyl)methanamine hydrochloride (0.445 g, 2.00mmol) was added. The reaction mixture was then again heated at refluxfor 19 h. The cooled reaction mixture was diluted with EtOAc, washedwith H₂O and brine, dried over anhydrous sodium sulfate and concentratedto dryness. The residue was purified on ISCO using a 40 g column (0-5%MeOH-DCM) to afford the title compound (0.20 g, 0.79 mmol, 40% yield) asan off-white solid. LC (Method B): 1.342 min. MS (APCI): calcd forC₁₀H₁₁BrN₃ [M+H]⁺ m/z 252.0, found 252.1. ¹H NMR (400 MHz, CDCl₃) δ ppm8.09 (s, 1H), 7.50-7.55 (m, 2H), 6.95-7.01 (m, J=8.61 Hz, 2H), 5.05 (s,2H), 2.39 (s, 3H).

Intermediate 459b:5-Fluoro-4′-((3-methyl-4H-1,2,4-triazol-4-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

In a 5 mL sealable vial, a solution of4-(4-bromobenzyl)-3-methyl-4H-1,2,4-triazole (0.148 g, 0.59 mmol) and4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(0.215 g, 0.87 mmol) in a mixture of ethanol (0.6 mL) and toluene (5.4mL) was purged with a stream of N₂ for 20 min. To this mixture was addedtetrakis(triphenylphosphine) palladium (0) (0.066 g, 0.057 mmol) and 2Maqueous Na₂CO₃ (0.88 mL, 1.760 mmol) and the mixture was stirred at 100°C. for 3.5 h. The cooled mixture was diluted in EtOAc and then filteredover Celite®. The filtrate was concentrated to dryness and the residuewas purified on ISCO using a 40 g column (0-10% MeOH-DCM) to afford thetitle compound (0.138 g, 0.47 mmol, 80% yield) as a yellowish solid. LC(Method B): 1.476 min MS (APCI): calcd for C₁₇H₁₄FN₄ [M+H]⁺ m/z 293.1,found 293.1. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.16 (s, 1H), 7.80 (dd,J=5.48, 8.22 Hz, 1H), 7.59 (d, J=8.22 Hz, 2H), 7.16-7.26 (m, 4H), 5.18(s, 2H), 2.44 (s, 3H).

Intermediate 459c:5-(4-Methyl-1H-pyrazol-1-yl)-4′-((3-methyl-4H-1,2,4-triazol-4-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

In a vial under N₂, a mixture of5-fluoro-4′-((3-methyl-4H-1,2,4-triazol-4-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.043 g, 0.15 mmol), 4-methyl-1H-pyrazole (0.020 mL, 0.24 mmol) andpotassium carbonate (0.047 g, 0.34 mmol) in DMF (2 mL) was heated at100° C. for 18 h. Additional 4-methyl-1H-pyrazole (0.020 mL, 0.24 mmol)was added and heating was continued at the same temperature for 3 days.The cooled reaction mixture was acidified with formic acid (0.050 mL)and this mixture was purified by reverse-phase preparative LC (MethodD). The product obtained was lyophilized from ACN-H₂O to afford thetitle compound (0.043 g, 0.12 mmol, 82% yield) as a white solid. LC(Method B): 1.698 min MS (APCI): calcd for C₂₁H₁₉N₆ [M+H]⁺ m/z 355.2,found 355.1. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.16 (s, 1H), 7.79-7.87 (m,3H), 7.74 (dd, J=1.90, 8.60 Hz, 1H), 7.61-7.66 (m, 2H), 7.60 (s, 1H),7.22-7.26 (m, 2H), 5.19 (s, 2H), 2.44 (s, 3H), 2.18 (s, 3H).

Example 459:5-(5-(4-Methyl-1H-pyrazol-1-yl)-4′-((3-methyl-4H-1,2,4-triazol-4-yl)methyl)-[1,1′-biphenyl]-2-yl)-2H-tetrazole

In a vial under N₂, a mixture of5-(4-methyl-1H-pyrazol-1-yl)-4′-((3-methyl-4H-1,2,4-triazol-4-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile(0.043 g, 0.12 mmol), dibutyltin oxide (0.038 g, 0.15 mmol) and TMS-N₃(0.160 mL, 1.21 mmol) in toluene (3.5 mL) was stirred at 120° C. for 17h. The cooled reaction mixture was poured into MeOH and this mixture wasconcentrated to dryness. The crude material was purified twice byreverse-phase preparative LC (Method D) and the product obtained waslyophilized from ACN-H₂O to afford the title compound (0.022 g, 0.056mmol, 47% yield) as a white solid. LC (Method B): 1.513 min MS (APCI):calcd for C₂₁H₂₀N₉ [M+H]⁺ m/z 398.2, found 398.1. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 8.53 (br s, 1H), 8.49 (s, 1H), 7.99 (d, J=7.4 Hz, 1H),7.92 (d, J=2.0 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.64 (s, 1H), 7.18 (s,4H), 5.23 (s, 2H), 2.27 (s, 3H), 2.11 (s, 3H).

Example 460:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2,6-dimethylpyrimidin-4(3H)-one

Intermediate 460a:5-bromo-4′-((2,4-dimethyl-6-oxopyrimidin-1(6H)-yl)methyl)-[1,1′-biphenyl]-2-carbonitrile

2,6-Dimethylpyrimidin-4(3H)-one (0.250 g, 2.014 mmol) was dissolved inDMF (3.66 ml). NaH (0.366 g, 9.15 mmol) was added and allowed to stirfor 15 min Intermediate 1-002 (0.643 g, 1.831 mmol) was added. Thereaction was stirred for 30 min and was diluted with EtOAc and washedwith saturated NH₄Cl then brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The material was purified by columnchromatography (ISCO, 40 g silica gel column, 25 minute gradient of 0 to100% EtOAc in hexanes) to yield Intermediate 460a (0.180 g, 0.456 mmol,25% yield) as a white solid. LC-MS (Method A2) RT=0.85 min, MS (ESI)m/z: 384.5 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.61 (m, 3H), 7.40 (s,2H), 7.03 (s, 2H), 6.46 (s, 1H), 5.48 (s, 2H), 2.61 (s, 3H), 2.42 (s,3H). Compound contains residual starting material.

Intermediate 460b:4′-((2,4-dimethyl-6-oxopyrimidin-1(6H)-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Intermediate 460a (0.400 g, 1.015 mmol), bis(pinacolato)diborane (0.515g, 2.029 mmol), X-Phos (0.048 g, 0.101 mmol), Pd₂(dba)₃ (0.093 g, 0.101mmol), and KOAc (0.498 g, 5.07 mmol) were dissolved in dioxane (10.15ml). The reaction was heated at 105° C. for one hour. The reaction wascooled to ambient temperature, diluted with EtOAc, filtered throughCelite, and concentrated in vacuo. The crude material was purified bycolumn chromatography (ISCO, 24 g silica gel column, 19 minute gradientof 0 to 100% EtOAc in DCM) to yield Intermediate 460b (0.235 g, 0.535mmol, 53%) LC-MS (Method A2) RT=0.65 min, MS (ESI) m/z: 360.0 (M+H)⁺.See mass of the boronic acid in LC-MS. ¹H NMR (400 MHz, CDCl₃) δ 7.85(dd, J=7.6, 1.0 Hz, 1H), 7.75 (d, J=7.7 Hz, 1H), 7.61-7.57 (m, 1H),7.55-7.50 (m, 2H), 7.43-7.38 (m, 2H), 6.46 (s, 1H), 5.48-5.45 (m, 2H),2.61 (s, 3H), 2.42 (s, 3H), 1.35 (s, 12H).

Intermediate 460c:4″-((2,4-dimethyl-6-oxopyrimidin-1(6H)-yl)methyl)-[1,1′:3′,1″-terphenyl]-4′-carbonitrile

Intermediate 460b (35 mg, 0.079 mmol), bromobenzene (37.4 mg, 0.238mmol), and 2nd Generation XPhos Precatalyst (6.24 mg, 7.93 μmol) weredissolved in toluene (0.1269 ml), EtOH (317 μl), and tripotassiumphosphate (79 μl, 0.159 mmol). The reaction was heated at 100° C. for 3hours. The reaction was diluted with EtOAc, filtered through Celite andconcentrated in vacuo. The crude material will be used as-is withoutfurther purification for the subsequent reaction. Intermediate 460c(0.030 g, 0.077 mmol, 97%). LC-MS (Method A2) RT=0.93 min, MS (ESI) m/z:392.2 (M+H)⁺.

Example 460:3-((6′-(2H-tetrazol-5-yl)-[1,1′:3′,1″-terphenyl]-4-yl)methyl)-2,6-dimethylpyrimidin-4(3H)-one

To a vial containing Intermediate 460c (0.030 g, 0.077 mmol) was addeddibutyltin oxide (50.9 mg, 0.204 mmol) and toluene (3 mL) followed byazidotrimethylsilane (0.068 mL, 0.511 mmol). The reaction mixture wassealed and heated at 100° C. behind a blast shield overnight. MeOH wasadded to the reaction followed by EtOAc. CAN (10% Aqueous) (560 mg,1.022 mmol) was added until gas evolution ceased. The layers wereseparated and the organic layer was washed with brine, dried with sodiumsulfate, and concentrated. The residue was dissolved in DMF, and thecrude material was purified via preparative LC-MS with the followingconditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile PhaseA: 5:95 ACN: H₂O with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5ACN: H₂O with 0.1% trifluoroacetic acid; Flow: 20 mL/min to yieldExample 460 (1.6 mg, 0.0036 mmol, 3.6% yield). LC-MS (Method A2) RT=0.82min, MS (ESI) m/z: 435.2. ¹H NMR (500 MHz, DMSO-d₆) δ 7.87 (br d, J=8.0Hz, 1H), 7.82 (br d, J=7.7 Hz, 2H), 7.80-7.76 (m, 2H), 7.52 (br t, J=7.5Hz, 2H), 7.47-7.43 (m, 1H), 7.41 (br d, J=7.8 Hz, 2H), 7.23 (br d, J=7.8Hz, 2H), 6.64 (s, 1H), 5.40 (s, 2H), 2.49 (s, 3H), 2.34 (s, 3H). Oneexchangeable proton not observed.

Example 461:2,6-dimethyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrimidin-4(3H)-one

Intermediate 461a:4′-((2,4-dimethyl-6-oxopyrimidin-1(6H)-yl)methyl)-5-(4-methylpyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Intermediate 460c usingIntermediate 460b (0.035 g, 0.079 mmol) and 2-bromo-4-methylpyridine(0.041 g, 0.238 mmol) to yield Intermediate 461a (0.030 g, 0.074 mmol,93%). LC-MS (Method A2) RT=0.72 min, MS (ESI) m/z: 407.1. Used withoutfurther purification in the next step.

Example 461:2,6-dimethyl-3-((5′-(4-methylpyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)pyrimidin-4(3H)-one

Synthesized in an analogous manner to Example 460 using Intermediate461a (0.030 g, 0.074 mmol). The crude material was purified viapreparative LC-MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂O with 0.1%trifluoroacetic acid; Flow: 20 mL/min to yield to yield Example 461.LC-MS (Method A2) RT=0.60 min, MS (ESI) m/z: 450.3.

Example 462:3-((5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-dimethylpyrimidin-4(3H)-one

Intermediate 462a:4′-((2,4-dimethyl-6-oxopyrimidin-1(6H)-yl)methyl)-5-(4-methoxypyridin-2-yl)-[1,1′-biphenyl]-2-carbonitrile

Synthesized in an analogous manner to Intermediate 460c usingIntermediate 460b (0.035 g, 0.079 mmol) and 2-bromo-4-methoxypyridine(0.044 g, 0.238 mmol) to yield Intermediate 462a (0.030 g, 0.071 mmol,90%). Used without further purification in the next step. LC-MS (MethodA2) RT=0.65 min, MS (ESI) m/z: 423.1.

Example 462:3-((5′-(4-methoxypyridin-2-yl)-2′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)methyl)-2,6-dimethylpyrimidin-4(3H)-one

Synthesized in an analogous manner to Example 460 using Intermediate462a (0.030 g, 0.071 mmol). The crude material was purified viapreparative LC-MS with the following conditions: Column: XBridge C18,19×200 mm, 5-μm particles; Mobile Phase A: 5:95 ACN: H₂O with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 ACN: H₂O with 0.1%trifluoroacetic acid; Flow: 20 mL/min to yield to yield Example 462(0.0008 g, 0.0014 mmol, 1.5%). LC-MS (Method A2) RT=0.57 min, MS (ESI)m/z: 466.2. ¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (d, J=5.6 Hz, 1H), 8.07 (brd, J=7.9 Hz, 1H), 8.03 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.54 (s, 1H),7.32 (br d, J=8.0 Hz, 2H), 7.27-7.21 (m, 2H), 6.96-6.92 (m, 1H), 6.65(s, 1H), 5.39 (s, 2H), 3.96-3.91 (m, 3H), 2.55 (s, 3H), 2.34 (s, 3H).One exchangeable proton not observed.

IV. BIOLOGY Methods Membrane Radioligand Binding Assay

In one aspect of the invention, AT1R biased agonist compounds wereassessed for their ability to directly interact with the AT1R or AT2R byusing isolated cell membranes to study the ability of these compounds tocompete with radiolabeled AII for binding to the receptor.

Membrane Preparation for Binding Assays

HEK293 cells stably expressing either the hAT1R or hAT2R were grown toconfluency in culture media (DMEM, 10% FBS, 1% Penicillin/streptomycin,250 μg/mL G418). Cells were washed with PBS, detached with 37° C. 5 mMEDTA in PBS, transferred to ice cold centrifugation tubes and pelletedfor 5 min at 300 g, 4° C. Cell pellets were re-suspended in coldhomogenization buffer (50 mM HEPES, pH 7.4 (KOH), 2 mM EDTA, proteaseinhibitor cocktail) and membranes were prepared by differentialcentrifugation (500 g for 5 min and then 45000 g for 20 min, at 4° C.)following cell lysis on ice with a Janke & 120 Kunkel Ultra-Turrax T25homogenizer at maximum speed, 3×7 seconds. The final pellet wasre-suspended in homogenization buffer, homogenized 3× with a 25 gneedle, frozen on dry ice and stored at −80° C.

Radioligand Binding Using the Scintillation Proximity Assays (SPA)Technology

Equilibrium competition assays were performed in incubation buffer (50mM HEPES pH 7.4 (KOH), 0.0001% (w/v) BSA, 10 mM MgCl₂) containing tensinglicate concentrations of competing ligands in DMSO (kept at ≤1% perincubation well), 5 nM [³H]angiotensin II (36.7 Ci/mmol, 1 mCi/mL), 15μg of membrane preparation and 0.5 mg SPA Wheat-Germ Agglutinin (WGA)beads, in a final volume of 100 μL. Total (T) and non-specific (NS)binding were determined in the absence and presence of 3 μM unlabelledangiotensin II, respectively. Assays were conducted for 60 min at roomtemperature with mixing. Bound radioactivity was counted in aPerkinElmer MicroBeta plate counter for 1 min per well, following a 30min adjustment in the dark. Under those conditions total binding was≤10% of total radioligand and the specific binding window (total minusnon-specific binding) was ≥8 fold. Non-recombinant HEK293 cell membranesshowed no specific binding window. Counts per minute (cpm) obtained fromthe counter were converted into percentage of [³H]angiotensin IIspecific binding according to the formula ((sample−NS)/(T−NS))*100.Sigmoidal concentration-response curves were generated by expressing thepercentage of residual specific binding as a function of competitorconcentration using a 4-parameter logistic equation (IDBS ActivityBasesoftware) to determine the IC₅₀ i.e. the concentration of competingligand necessary to reduce specific radioligand binding by 50%. Finally,the competing ligand binding affinities (K_(i)) were calculated fromIC₅₀/(1+([radioligand]/K_(d)), where K_(d) is the angiotensin IIaffinity constant, determined previously by saturation analysis (n=4).

Signaling Assays

In one aspect of the invention, signaling bias of compounds was assessedby comparing the relative activity of compounds to activate both theβ-arrestin and Gq signaling pathways. In order to confirm signalingbias, compounds were studied in two different assay formats.

DiscoveRx β-arrestin2 Recruitment and IP1 Assays

β-arrestin2 recruitment to activated receptors can be assessed using anenzyme complementation method (Zhao, Jones et al. 2008). In this case,the enzyme complementation assay utilized the DiscoveRx (Fremont,Calif.) Pathunter CHO-K1 AGTR1 β-arrestin cell line and accompanyingdetection reagents. Cells (5000/well) were plated into 1536 well plates(Cellocoat plates, Greiner Bio One, Monroe, N.C.) 14-16 hours beforeeach experiment in 20 μl DMEM/F12 medium (Thermo-Fisher Scientific,Carlsbad, Calif.) containing heat-inactivated 1% fetal bovine serum.Subsequently, the compounds of interest were added at varyingconcentrations to the wells in a volume of 200 nl and the cellsincubated for 90 min at 37° C. The detection reagent (10 μl) was addedto each well and the plates incubated at room temperature for 1 hourbefore measurement of chemiluminescence using an EnVision MultilabelReader (Perkin-Elmer, Waltham, Mass.). The data are processed usingToolset for Runmaster QCMulti. Concentration-response curves are fittedand EC₅₀s (agonist mode) and IC₅₀s (antagonist mode) estimated using a4-parameter logistic equation. Compound activities are reported as arelative percentage to the maximal effect of AII in the assays.

Gq activation can be assessed by measuring the accumulation of inositolphosphates (e.g. IP3, IP1) that are liberated following activation ofphospholipase C by Gq (Thomsen, Frazer et al. 2005). In the currentinvention we have utilized the DiscoveRx Pathunter CHO-K1 AGTR1β-arrestin cell line to also measure IP1 accumulation in response tocompounds. IP1 accumulation was measured in both agonist and antagonistmodes. In agonist mode, cells are plated as above 14-16 hours before theexperiment. The medium is then removed and compounds at varyingconcentrations added in a final volume of 20 μl. The cells are incubatedat 37° C. for 90 min IP1 accumulation detected using a commercial HTRFassay according to manufacturer's instructions (Cisbio, Bedford, Mass.).Specifically, 4 μl of D2-conjugate solution (diluted 1:20 in Cisbio HTRFassay buffer) is added to each well, followed by the addition of 4 μl ofanti-IP1 cryptate diluted 1:20 in HTRF assay buffer and the platesincubated for 20 min at room temperature. 14 μl from each well ismeasured using an Envision multi-label reader and data processed usingToolset for Runmaster QCMulti. Concentration-response curves are fittedand EC₅₀s (agonist mode) and IC₅₀s (antagonist mode) estimated using a4-parameter logistic equation. Compound activities are reported as arelative percentage to the maximal effect of AII in the assays.

The ability of compounds to antagonize the AII IP1 response in thisassay is measured by pre-incubating cells for 30 min in 10 μl of HTRFassay buffer at 37° C. followed by the addition of 10 μl of 1 nM AII toeach well and the plates incubated at 37° C. for 90 min Detection andmeasurement of fluorescence is performed as above. Compound activity isreported as percent inhibition of the effect of AII alone.

BRET β-Arrestin2 and Gq Activation Assays

In another aspect of the invention, association of the AT1R withsignaling proteins is assessed using bioluminescence resonance energytransfer assays (Stephane Angers, Ali Salahpour et al. 2002). Thistechnology measures the association between bioluminescent andfluorescent protein tags.

Materials

Several of the plasmid constructs used in BRET experiments werepreviously described. Briefly, the coding sequence of β-arrestin2 wasfused to Renilla luciferase II to generate β-arrestin2-Rluc (Quoyer,Janz et al. 2013). The membrane targeting motif from K-Ras, CAAX motif(GKKKKKKSKTKCVIM), was fused to Renilla GFP to create rGFP-CAAX plasmid(Namkung Y et al., Nat Commun (2016) 7, 12178). The Renilla luciferaseII was inserted in the Gαq protein to generate Gαq-Rluc (Breton,Sauvageau et al. 2010). The Gγ1 protein was tagged with GFP10 to obtainGFP-Gγ1, using the same strategy described previously for GFP-Gγ2(Gales, Rebois et al. 2005). The Gαq binding domain of the p63RhoGEFprotein (amino acids 295-502) was fused to Renilla luciferase II tocreate P63-Rluc. Finally, the hAT1R plasmid construct encoding thereceptor was generated by optimizing the coding sequence of humanangiotensin II receptor (GeneOptimizer from ThermoFisher), and adding anartificial cleavable signal peptide from bovine prolactin(MDSKGSSQKGSRLLLLLVVSNLLLCQGVVS) in N-terminus of the receptor toincrease cell surface expression.

Protocols

β-arrestin2 Biosensor Assay

The BRET β-arrestin2 assay was studied in two separate formats whichdiffered in the expression level of AT1R. For higher receptorexpression, cells were transfected with 5 ng/well of plasmid DNA and forlower receptor expression cells were transfected with 0.04 ng/well ofplasmid DNA. In either case, HEK293 cells were cultured in DMEMsupplemented with Penicillin-Streptomycin and 10% fetal bovine serum.Two days before the BRET experiment, HEK293 cells were transfected withhAT1R (5 ng/well or 0.04 ng/well) as well as β-arrestin2-Rluc (1.25ng/well) and rGFP-CAAX (12.5 ng/well) using linear polyethylenimine 25kDa (PEI) at a PEI:DNA ratio of 3:1. Transfected cells were directlyseeded in 384-well plates, at a density of 10 000 cells per well, andmaintained in culture for the next 48 h.

BRET experiments were carried out subsequently using the followingprocedures: cells were washed once with Tyrode's buffer (137 mM NaCl, 1mM CaCl₂, 0.9 mM KCl, 1 mM MgCl₂, 3.6 mM NaH₂PO₄, 5.5 mM glucose, 12 mMNaHCO₃, and 25 mM HEPES, pH 7.4) and 20 μl of Tyrode's buffer was addedto each well. Cells were equilibrated in their new buffer at roomtemperature for at least 30 minutes. Following the equilibration period,the coelenterazine substrate was first added to the cells, 10 μl perwell of a 3× solution of prolume purple coelenterazine (finalconcentration of 2 μM), immediately followed by compound addition usingthe HP D300 digital dispenser from Tecan (10 singlicate concentrations).Cells were incubated for 15 min at room temperature and BRET readingswere then collected using a Spark10M multimode reader from Tecan withBRET2 filters 360-440/505-575, to record agonist response. The BRETsignal was determined by calculating the ratio of the light emitted byGFP (505-575 nm) over the light emitted by the Rluc (360-440 nm). BRETsignal values were converted into percentage of activation using thenon-stimulated control as 0% and AngII maximal response as 100%.Sigmoidal concentration-response curves were generated with thosenormalized values using a 4-parameter logistic equation (IDBSActivityBase software), to determine EC₅₀ of the different compounds.

Gq Biosensor Assay

HEK293 cells were cultured in DMEM supplemented withPenicillin-Streptomycin and 10% fetal bovine serum. Two days before theBRET experiment, HEK293 cells were transfected with hAT1R expressionplasmid (200 ng/well) as well as Gαq-Rluc (100 ng/well), G131 (375ng/well) and GFP-Gγ1 (625 ng/well), using linear polyethylenimine 25 kDa(PEI) at a PEI:DNA ratio of 3:1. Transfected cells were directly seededin 96-well plates, at a density of 35 000 cells per well, and maintainedin culture for the next 48 h.

BRET experiments were carried out subsequently using the followingprocedures: cells were washed once with Tyrode's buffer (137 mM NaCl, 1mM CaCl₂, 0.9 mM KCl, 1 mM MgCl₂, 3.6 mM NaH₂PO₄, 5.5 mM glucose, 12 mMNaHCO₃, and 25 mM HEPES, pH 7.4) and 90 μl of Tyrode's buffer was addedto each well. Cells were equilibrated in their new buffer at roomtemperature for at least 30 minutes. Following the equilibration period,the coelenterazine substrate was first added to the cells, 10 μl perwell of a 10× solution (prolume purple coelenterazine at a finalconcentration of 2 μM), immediately followed by compound addition usingthe HP D300 digital dispenser from Tecan (10 singlicate concentrations).Cells were incubated for 5 min at room temperature and BRET readingswere then collected using a Synergy Neo Multi-Mode reader from BioTekwith

BRET2 filters 410/515, to record agonist response. Cells were thenfurther incubated at room temperature for an additional 20 min (for atotal of 25 min pre-incubation period with the compounds), beforeaddition of a fixed dose of AngII corresponding to the EC₈₀. A secondreading was collected 5 min after this second addition, using theSynergy Neo Multi-Mode reader from BioTek with BRET2 filters 410/515, torecord antagonist response. The BRET signal was determined bycalculating the ratio of the light emitted by GFP (515 nm) over thelight emitted by the Rluc (410 nm). To analyze agonist response, BRETsignal values were converted into percentage of activation using thenon-stimulated control as 0% and AngII maximal response as 100%.Sigmoidal concentration-response curves were generated with thosenormalized values using a 4-parameter logistic equation (IDBSActivityBase software), to determine EC₅₀ of the different compounds. Inthe case of antagonist response analysis, BRET signal values wereconverted into percentage of inhibition using the fixed dose of AngII(corresponding to the EC₈₀) as 0% and non-stimulated control as 100%.Sigmoidal concentration-response curves were generated with thosenormalized values using a 4-parameter logistic equation (IDBSActivityBase software), to determine IC₅₀ of the different compounds.

P63 Rho-GEF Biosensor Assay

Assessment of Gq signaling activation was also determined using analternative BRET format targeting the recruitment of P63 Rho-GEFfollowing activation of Gq. This was performed in both agonist andantagonist modes.

HEK293 cells were cultured in DMEM supplemented withPenicillin-Streptomycin and 10% fetal bovine serum. Two days before theBRET experiment, HEK293 cells were transfected with hAT1R (0.04 ng/well)as well as P63-Rluc (1.25 ng/well) and rGFP-CAAX (12.5 ng/well) usinglinear polyethylenimine 25 kDa (PEI) at a PEI:DNA ratio of 3:1.Transfected cells were directly seeded in 384-well plates, at a densityof 10 000 cells per well, and maintained in culture for the next 48 h.

BRET experiments were carried out subsequently using the followingprocedures: cells were washed once with Tyrode's buffer (137 mM NaCl, 1mM CaCl₂, 0.9 mM KCl, 1 mM MgCl₂, 3.6 mM NaH₂PO₄, 5.5 mM glucose, 12 mMNaHCO₃, and 25 mM HEPES, pH 7.4) and 20 μl of Tyrode's buffer was addedto each well. Cells were equilibrated in their new buffer at roomtemperature for at least 30 minutes. Following the equilibration period,the coelenterazine substrate was first added to the cells, 10 μl perwell of a 3× solution of prolume purple coelenterazine (finalconcentration of 2 μM), immediately followed by compound addition usingthe HP D300 digital dispenser from Tecan (10 singlicate concentrations).Cells were incubated for 15 min at room temperature and BRET readingswere then collected using a Spark10M multimode reader from Tecan withBRET2 filters 360-440/505-575, to record agonist response. Cells werethen further incubated at room temperature for an additional 10 min (fora total of 25 min pre-incubation period with the compounds), beforeaddition of a fixed dose of AngII corresponding to the EC₈₀. A secondreading was collected 15 min after this second addition, using aSpark10M multimode reader from Tecan with BRET2 filters 360-440/505-575,to record antagonist response. The BRET signal was determined bycalculating the ratio of the light emitted by GFP (505-575 nm) over thelight emitted by the Rluc (360-440 nm). BRET signal values wereconverted into percentage of activation using the non-stimulated controlas 0% and AngII maximal response as 100%. Sigmoidalconcentration-response curves were generated with those normalizedvalues using a 4-parameter logistic equation (IDBS ActivityBasesoftware), to determine EC₅₀ of the different compounds. In the case ofantagonist response analysis, BRET signal values were converted intopercentage of inhibition using the fixed dose of AngII (corresponding tothe EC₈₀) as 0% and non-stimulated control as 100%. Sigmoidalconcentration-response curves were generated with those normalizedvalues using a 4-parameter logistic equation (IDBS ActivityBasesoftware), to determine IC₅₀ of the different compounds.

Rat Isolated Aortic Ring Assay

Male rats approximately 225-250 g were euthanized according to IACUCguidelines. The thoracic aorta was quickly removed and placed in coldbicarbonate-buffered physiological salt solution (PSS) containing: 118.4mM NaCl, 4.6 mM KCl, 1.2 mM KH₂PO₄, 1.2 mM MgSO₄, 1.9 mM CaCl₂), 25.0 mMNaHCO₃, and 10.1 mM glucose. Adherent connective tissue was carefullyremoved and rings cut into approximately 3 mm width. The endothelium wasremoved from the ring by sliding it onto a dissecting probe and gentlyrolling on filter paper saturated with PSS. Each ring was individuallymounted for isometric force recording using stainless steel pin supportson a DMT720MO Tissue Bath System (ADInstruments; one pin supportconnected to the force transducer and the other pin support connected toa micrometer) for control of tissue length and a Power Lab Chart Pro8/35 for transducer. The rings were mounted on pin supports inindividual 8 ml chambers containing PSS maintained at 37° C. and aeratedwith 95% O₂-5% CO₂. Mechanical responses were recorded using a PowerLabsystem.

The aortic rings were gradually stretched over a 2 hr equilibrationperiod to a preload of 2 g which was maintained throughout theexperiment. During this equilibration period, the rings were stimulatedwith 20 mM KCl to determine contractility. The absence of theendothelium was then determined by contracting the rings withphenylephrine (PE; 30 nM) until a steady state level of contraction wasattained. Subsequently, 1 μM acetylcholine (Ach) was added to each ringto induce relaxation. If relaxation was observed, it was gently rubbedagain to remove any remaining endothelium. The rings were thenextensively washed until the tension returned to the preload of 2 gprior to the start of the experimental protocol.

The rings were pretreated (20 min) with test articles to determine theeffects on baseline contraction. A concentration-response curve for Allwas performed in the absence and presence of varying concentrations oftest compounds by exposing the ring to increasing concentrations of thehormone and determining the contractile response. Betweenconcentrations, the force was allowed to increase to a steady statelevel before the addition of the next concentration (approximately 5min). If no change in force was detected after a 5 min exposure to agiven concentration, the next higher concentration was administered.After the highest concentration, 60 mM KCl was added to assess thetissue's maximal contractile response.

All force determinations were made assuming the level of force onbaseline is zero and the maximal force attained in the presence of AIIalone (control ring) is 100%. Force is reported relative to theselevels. The EC50 values (the concentration of AII or compound thatinduces 50% of the maximal response in that tissue) were determinedusing a four-parameter logistic equation using EXCELFit software. Therelative contraction of AII max/KCl is also determined to gauge whethera given compound affects the max contraction by AII. Schild plotanalysis was performed for any compounds which induced a significantshift to the right of the AII concentration-response curve.

Rat Isolated Working Heart Preparation

Sprague-Dawley rats (250-300 g) were anesthetized with ketamine/xylazine(25 mg/kg/15 mg/kg IM, respectively) and heparin (200 U/kg, IV). Afterinduction of anesthesia, the trachea was exposed, intubated and theanimal mechanically ventilated with room air. A mid-sternal thoracotomywas made and the ribs retracted to expose the heart. The pericardium wasremoved and the aorta cleared of any connective tissue. A silk suturewas placed around the aorta before its bifurcation. The inferior venacava was clamped just above the diaphragm and a cannula quickly insertedinto the aorta and secured with suture. While being ventilated, heartswere perfused in situ with the cannula via retrograde perfusion of theaorta. The cannula was connected to a reservoir containing oxygenatedKrebs-Henseleit bicarbonate buffer with the following composition: 118mM NaCl, 4.0 mM KCl, 0.4 mMNaH₂PO₄, 1.1 mM MgCl₂, 1.8 mM CaCl₂, 22 mMNaHCO₃, 5.0 mM glucose, 0.038 mM creatine and 2.0 mM pyruvic acid at pH7.4. Once the heart was perfused, it was carefully excised from thechest and transferred to the isolated heart apparatus and perfused inLangendorff mode with the buffer solution at a constant pressure (70mmHg) and temperature (38±0.2° C.). The ambient temperature around thepreparation was maintained by a heated vessel. During this time, a smallincision was made in the left atrium into which another cannula wasinserted and tied off. This non-working preparation was run for 10minutes and then converted to a working system by switching the supplyof perfusate from the aorta to the left atrial cannula at a hydrostaticpressure of 12 mmHg (pre-load). The working heart ejected perfusatethrough the aortic valve into the aortic cannula. The hydrostaticpressure in the aortic cannula was maintained at 70 mmHg (after-load)throughout the working phase. A Millar catheter (840-4079) was insertedinto the left ventricle for recording of left ventricular pressure(LVP), contractility (+dp/dt max) and lusitropy (−dP/dt min).

After a 20 min equilibration period, hearts underwent 10 min of globalisothermic ischemia, and 60 min of post-ischemic reperfusion. The heartswere randomly assigned to one of two groups: (1) control (withoutcompound); (2) compound perfused in the 60 min post-ischemic period.Left atrial and aortic flow were measured using in-line ultrasonic flowprobes; stroke volume was estimated using aortic flow and heart rate.All measured data was stored and analyzed by PLUGSYS Modular and Ponemahphysiology platform systems.

Acute Rat Cardiac Function Testing

Surgical Preparation

Male Sprague Dawley rats (200-300 g) were anesthetized withketamine-xylazine cocktail. The trachea was intubated and ventilatedwith oxygenated room air. The left side of the chest was clipped of hairand disinfected according to standard aseptic procedure. The rat wasplaced on a warm surgical table and a small incision made at the levelof the 4th and 5th intercostal space. A loose purse string pocketsurrounding the incision was formed by using vicryl suture with taperneedle threaded through the skin and muscle layers. A lateralthoracotomy was performed, the region containing the left descendingcoronary artery was identified, and a 6-0 silk suture with taper needlewas quickly threaded under the LAD and tied permanently with a doubleknot. Myocardial infarction was verified by blanching of the tissuefollowing vessel ligation. Following the closure of the skin and musclelayer using the purse-string suture with evacuation of the pneumothorax,the rat was given an analgesic agent, kept in the recovery hood for 24hours, and transferred back to the housing unit. Animals were maintainedfor 4 weeks following surgery. Reduced cardiac function of each animalwas confirmed by ultrasound imaging prior to being placed into a study.

On the day of the study, rats were anesthetized with 4% isoflurane andsurgical anesthesia was maintained with 1.5%-2% isoflurane. The leftfemoral artery was exposed, isolated and catheterized with a MillarSPR-671 (1.4 F) pressure catheter which was advanced into the abdominalaorta for measurement of aortic blood pressure. The right jugular veinand the right common carotid artery were exposed via a midline incisionin the ventral neck. The right jugular vein was cannulated with a lengthof PESO for administration of test substances. The right carotid arterywas catheterized with a 2 F Millar pressure-volume transducer (modelSPR-838) which was advanced into the left ventricle for measurement ofcardiac left ventricular pressure and conductance.

Hemodynamic Analyses

Following completion of the surgical preparation, animals were allowedto equilibrate prior to administration of vehicle or test article forapproximately 10-15 min. Animals without stable ventricular conductanceduring this equilibration period were not used. Vehicle or compoundswere administered via intravenous infusion for 15 min. During thisperiod, the following parameters were measured and collected usingLabChart 7 software (AD Instruments, Colorado Springs, Colo.): heartrate, aortic blood pressure and ventricular pressure. Stroke volume,cardiac output, pressure-volume loops, +dP/dt and τ were automaticallycalculated from the collected data by the software. Following theinfusion, saline calibration (for calculation of parallel conductance,Vp) was performed according to manufacturer's instructions (ADInstruments). From one rat, at the end of the experiment 3 ml of bloodwas withdrawn from the abdominal vena cava onto 0.1 ml heparin (1000u/ml) and used to construct a standard curve of volume vs. conductance.The equation for the line constructed through these points was used tocalculate volume from the conductance data collected during theexperiment. This equation was used to calculate volume data from theconductance data collected from the subsequent rats run that day.

Statistical analysis to determine differences was performed on the dataaveraged over the entire 15 min infusion period by Students t-testcomparing vehicle and compound treatment data.

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Compounds were tested in the assays described above with the followingresults:

DiscoveRx DiscoveRx Example β-arrestin2 β-arrestin2 Numbe EC₅₀ (nM) Ymax(%) 1 15.5 44.1 2 19.8 21.8 3 21.2 22.9 4 7.5 48.9 5 14.5 30.9 6 14.127.0 7 14.4 21.6 8 6.0 42.2 9 3.7 66.7 10 1.4 60.3 11 9.9 36.3 12 6.321.4 13 12.9 24.8 14 10.3 20.8 15 22.6 14.9 16 59.8 17.1 17 15.7 11.9 18139.9 54.2 19 7.5 57.9 20 4.9 38.7 21 22.1 21.1 22 10.3 14.8 23 54.126.8 24 13.4 24.1 25 15.9 23.1 26 10.8 25.0 27 205.8 10.6 28 321.7 11.929 8.6 29.8 30 4.9 48.0 31 33.9 55.1 32 34.3 86.1 33 9.7 29.9 34 40.335.6 35 64.0 28.2 39 33.1 23.3 40 9.3 36.4 45 24.6 60.3 46 32.0 45.1 4710.1 24.5 48 106.3 20.6 49 10.9 47.6 50 10.9 21.8 51 21.2 21.1 52 5.55.0 53 2.6 39.4 54 5.9 39.5 55 9.3 44.9 56 58.3 20.8 57 16.6 26.3 5886.2 12.7 59 12.5 29.5 60 53.7 33.5 61 31.5 43.7 62 15.1 50.0 63 10.226.1 64 6.9 67.8 65 27.3 31.0 66 5.8 25.8 67 19.3 30.9 69 376.0 8.5 7013.1 58.7 71 17.4 46.8 72 22.6 63.6 73 107.9 26.4 74 390.6 3.9 75 543.27.1 76 840.2 13.2 77 60.2 21.1 78 19.9 50.0 79 285.9 31.7 80 73.4 33.581 38.3 17.6 82 95.7 16.8 83 23.9 40.5 84 91.6 35.3 85 18.2 16.9 86158.8 38.0 87 42.5 16.7 88 8.1 22.1 89 49.4 22.5 90 55.4 23.2 91 60.622.6 93 7.9 32.6 94 13.1 35.9 95 137.3 21.0 96 12.6 33.0 97 15.1 34.3 9818.8 72.9 99 32.4 6.3 100 28.8 12.7 101 30.0 21.4 102 44.4 41.0 103111.7 8.8 104 116.1 9.1 105 16.0 31.0 106 17.6 6.3 107 26.7 24.6 10842.3 38.8 109 19.6 17.4 110 35.9 26.9 111 6.4 63.3 112 124.4 33.4 11314.9 66.3 114 49.9 46.5 115 13.3 30.8 116 14.1 42.1 117 74.0 30.6 11866.0 50.0 119 47.5 51.4 120 12.5 44.5 121 302.4 47.4 122 16.1 33.8 1239.7 4.9 124 64.9 28.1 125 45.3 16.6 126 5.3 17.3 128 25.7 14.5 129 33.512.9 130 21.9 31.2 131 13.7 19.1 132 87.2 14.1 133 5.7 18.0 134 73.540.3 135 13.7 38.6 136 4.9 43.2 137 >100000 138 13.4 27.9 139 10.5 50.1140 9.7 22.1 141 13.5 31.5 142 27.5 22.7 143 8.4 47.4 144 12.3 33.3 14527.3 36.3 146 31.6 34.0 147 107.1 23.0 148 103.2 34.8 149 38.9 55.2 15013.7 45.6 151 76.4 44.3 152 11.6 28.6 153 28.7 19.6 154 14.1 48.7 15540.8 32.0 156 85.1 19.9 157 30.3 44.7 158 191.1 41.6 159 51.4 44.0 16087.8 50.2 161 88.5 40.7 162 147.3 31.9 163 69.2 34.6 164 76.0 58.7 16556.8 45.7 166 23.1 47.5 167 36.0 78.8 168 352.4 34.5 169 110.7 50.1 170170.2 63.4 171 33.5 38.6 172 196.5 27.1 175 6.0 37.0 176 31.8 32.0 17711.8 52.2 178 7.1 75.6 179 40.7 58.3 180 51.9 40.4 181 48.0 88.8 18284.9 74.2 183 66.2 36.2 184 31.0 51.2 185 138.8 48.9 186 11.8 55.6 18744.4 34.0 188 41.7 53.3 189 9.2 53.0 190 137.7 57.0 191 20.7 53.0 19294.3 45.1 193 52.2 60.7 194 63.2 36.6 195 694.3 77.6 196 3015.8 50.4 197282.3 20.2 198 122.1 33.0 199 273.0 34.2 200 708.9 25.1 201 348.2 7.0202 1114.0 19.4 203 161.8 32.3 204 26.4 42.4 205 31.8 42.2 206 11.1 21.2207 11.5 23.1 208 20.8 44.8 209 45.9 49.6 210 8.6 48.4 211 96.8 21.2 21210.1 11.2 213 215.3 27.3 214 76.1 74.1 215 5.1 46.1 216 9.6 33.4 217 4.670.3 218 45.9 21.5 219 35.2 21.6 222 56.9 42.7 225 29.0 35.4 226 242.317.5 227 32.0 51.6 228 30.4 32.1 229 39.0 24.0 230 63.1 16.7 231 28.736.8 232 16.9 41.5 233 10.5 59.2 234 9.2 59.9 235 56.6 56.0 236 12.560.8 237 55.3 62.3 238 198.1 22.4 239 5.4 59.1 240 48.6 42.0 241 41.544.3 243 22.4 37.7 244 96.5 34.7 245 114.7 75.5 246 234.2 38.3 247 6.930.8 248 26.5 18.2 249 23.8 34.2 250 23.0 43.9 251 33.6 20.2 252 34.315.8 253 31.2 37.2 254 35.8 26.9 255 122.8 26.3 257 9.0 34.9 258 23.135.2 259 12.9 80.6 260 51.7 36.4 261 136.6 17.3 262 19.9 50.8 264 19.252.9 265 30.1 53.4 266 64.3 75.8 267 9.8 62.5 268 628.3 39.8 269 6542.614.2 270 6551.9 28.6 271 383.7 45.5 272 16.5 43.5 273 21.4 39.3 274251.4 37.5 275 26.6 50.9 276 50.0 50.9 277 36.1 46.0 278 45.1 51.9 279189.8 33.7 280 904.4 35.2 281 41.6 47.4 283 44.5 57.5 284 21.1 62.7 28566.4 24.8 286 113.1 35.8 287 175.2 30.5 288 185.8 29.6 289 48.2 51.1 29088.5 30.7 291 134.4 10.0 292 177.0 32.1 293 186.9 40.4 294 87.3 28.9 29547.5 60.3 296 127.9 41.8 297 142.2 30.5 298 277.5 31.3 299 7.7 83.0 30210.2 61.1 303 42.3 58.9 305 25.5 69.3 308 29.1 51.8 309 4.1 80.4 31014.9 51.4 311 3.9 77.6 312 22.5 79.9 313 28.1 46.1 314 3.5 66.8 315242.3 21.5 316 53.0 51.6 317 87.2 51.5 318 47.5 54.6 319 71.1 49.0 32040.7 55.7 321 56.8 83.4 322 39.2 33.7 323 22.2 43.2 324 17.4 55.2 3269.5 45.9 327 9.4 64.2 328 801.8 51.8 329 7.1 77.6 330 13.2 57.8 331 13.244.5 332 24.1 30.6 333 10.0 67.8 334 10.8 73.5 335 36.1 22.7 336 16.461.4 337 40.6 85.6 338 17.8 68.9 339 10.6 58.0 345 18.1 44.8 346 13.044.5 347 57.2 26.8 348 7.3 50.9 349 69.2 24.8 350 8.3 47.0 351 18.0 45.4352 234.3 35.7 353 55.0 22.4 354 59.9 48.3 355 8.6 42.4 356 27.3 41.5357 19.6 41.8 358 10.1 40.2 359 17.4 43.5 360 29.2 37.2 361 97.8 29.3362 123.3 49.8 363 10.7 46.2 364 23.2 30.3 365 46.2 39.7 366 11.1 37.0367 5.7 35.9 368 59.8 39.1 369 174.4 30.9 370 16.3 26.8 371 5.7 40.8 37258.8 41.7 373 14.2 29.5 374 10.5 44.3 375 89.7 35.8 376 18.5 22.1 37749.5 39.0 378 106.9 15.7 379 21.2 30.2 380 59.2 43.1 381 343.8 37.4 38213.2 27.6 383 70.4 22.8 384 8.0 49.3 385 31.4 35.4 386 8.4 27.3 387 16.632.8 388 44.7 71.7 389 91.8 26.7 390 11.8 53.5 391 45.8 23.3 392 45.229.2 393 9.1 41.2 394 365.3 59.1 395 16.1 54.1 396 5.0 57.8 397 78.246.5 398 12.7 53.6 399 13.4 45.8 400 149.8 40.4 401 544.3 43.7 402 9.957.0 403 14.2 61.4 404 9.6 38.6 405 57.5 32.8 406 9.0 33.9 407 173.424.6 408 23.3 32.5 409 59.3 50.6 410 26.9 41.9 411 30.9 56.4 412 11.764.1 413 21.8 16.3 414 166.3 21.5 415 110.8 29.3 416 18.0 29.5 417 5.939.6 418 67.8 31.2 419 120.7 33.9 420 6.5 73.6 421 9.4 38.5 422 68.726.7 423 22.9 22.8 424 99.3 28.6 425 27.3 54.2 426 34.2 52.5 427 89.919.6 430 33.2 55.2 431 194.3 26.0 432 40.1 42.9 433 59.1 49.6 434 72.040.9 435 1407.3 19.1 436 993.5 31.2 437 3916.7 26.4 438 20.4 41.7 439108.5 26.4 440 241.2 13.6 441 100.6 39.3 442 104.7 10.9 443 124.4 36.5444 125.2 36.3 445 37.7 61.2 446 179.3 29.8 447 294.7 35.0 448 160.520.8 449 263.0 17.8 450 479.4 23.1 451 23.3 11.4 452 8.1 36.1 453 31.459.5 454 22.7 11.2 455 46.8 14.4 BRET β-Arrestin2 BRET β-Arrestin2Example High AT1R Expression High AT1R Expression Number EC₅₀ (nM) Ymax(%) 1 7.2 86.9 2 11.3 74.2 3 14.9 79.6 4 3.8 95.4 5 16.0 76.2 6 51.073.5 7 37.4 60.0 8 4.1 93.0 9 5.6 87.8 10 1.4 86.9 11 22.0 79.2 12 9.083.6 13 11.5 53.8 16 24.7 69.9 19 2.4 89.8 20 4.3 85.5 21 51.4 64.0 2233.7 57.1 23 170.5 66.3 24 13.5 73.1 25 19.8 74.5 27 89.5 20.1 29 11.382.7 30 5.6 87.5 31 58.2 85.5 32 5.1 91.6 33 16.5 83.0 34 50.6 68.4 35147.7 76.7 39 18.8 37.9 40 14.0 84.6 45 34.7 92.2 46 13.1 84.8 47 14.756.6 48 40.6 43.8 49 11.2 78.3 50 16.8 64.9 51 99.0 43.8 52 30.7 23.4 535.4 90.6 54 5.7 89.7 56 48.9 63.0 57 15.2 66.3 58 190.3 46.2 59 14.052.1 60 19.6 85.8 61 16.1 81.4 63 7.5 76.6 64 1.9 92.5 69 1504.5 10.3 707.1 94.7 71 23.3 86.6 72 33.2 85.8 74 >100000 3.2 75 1124.5 53.9 77 90.677.1 78 15.0 94.3 82 142.5 49.6 83 52.1 87.3 84 36.4 88.9 85 10.5 88.387 451.2 29.1 90 27.7 77.7 93 7.5 82.8 94 20.8 76.8 96 12.9 77.6 97 31.179.7 98 20.3 86.6 99 144.4 9.6 100 155.1 19.4 102 99.6 71.6 104 345.823.4 105 28.9 58.0 106 138.2 12.4 107 225.9 54.3 109 73.1 59.9 112 30.678.5 114 11.9 89.2 117 94.2 35.0 121 431.1 98.0 122 17.5 94.3 123 65.320.6 124 137.8 32.6 125 300.0 15.1 126 47.1 65.1 127 23.6 82.7 128 132.911.0 129 240.0 40.7 130 26.1 80.0 131 49.0 42.5 132 496.2 22.0 133 38.469.0 134 157.7 77.0 135 28.7 94.8 136 9.9 94.2 137 35.3 12.2 138 56.973.2 139 11.2 95.0 141 10.0 88.6 142 59.2 82.9 143 8.2 94.6 144 26.8104.0 145 64.4 81.5 146 38.2 85.6 147 126.5 66.6 148 90.4 72.8 149 24.185.7 175 5.2 93.0 176 25.5 79.1 177 4.0 91.8 178 4.8 89.3 179 20.7 90.6180 50.8 85.3 181 4.8 94.1 182 7.0 90.4 183 62.9 90.0 184 14.7 85.9 185149.1 86.7 190 83.6 88.8 195 100.6 87.0 196 617.8 83.3 198 428.3 95.8199 223.1 88.5 200 1777.7 54.3 202 1620.6 52.0 203 123.8 79.1 204 3.685.9 205 4.8 92.1 206 15.8 57.9 207 22.0 74.8 208 6.0 103.1 209 7.2 90.6210 9.0 88.2 211 67.0 80.2 212 10.6 29.2 213 92.9 89.9 214 4.2 86.5 22510.9 82.1 226 348.4 35.0 227 7.4 87.8 228 31.9 93.1 229 25.7 82.1 23061.2 53.5 234 3.4 93.3 235 29.6 89.5 236 3.6 93.3 237 16.3 84.4 238280.7 62.6 245 4.9 88.8 247 13.8 74.4 248 14.0 79.5 249 8.0 80.3 250 3.879.8 251 10.6 57.2 252 29.4 41.4 253 17.9 85.3 254 20.0 75.6 255 24.380.2 257 10.0 87.3 258 41.5 75.7 259 6.9 83.2 260 7.8 87.9 261 40.0 62.3268 1034.6 73.8 269 30667.7 58.7 270 12881.4 74.3 271 560.9 80.3 27215.2 84.0 273 23.2 88.1 274 279.1 82.5 275 21.5 71.5 276 77.9 73.6 27728.9 79.4 278 13.0 87.2 279 209.6 82.6 280 699.5 75.7 281 10.5 93.1 28322.8 88.5 284 33.0 92.9 285 57.3 33.4 286 47.1 45.3 287 54.1 45.9 288474.3 69.2 289 13.0 85.2 290 67.3 31.2 291 1645.6 9.6 292 72.2 36.5 293135.8 70.2 294 150.0 24.7 295 14.0 92.5 296 68.8 79.9 297 327.4 74.5 298269.7 68.8 311 1.5 92.0 312 2.6 91.8 313 7.7 92.9 314 5.8 90.3 3151838.6 29.1 316 46.2 97.5 317 319.3 39.8 318 131.6 93.9 320 172.6 86.8321 108.2 86.7 322 8.4 80.9 329 2.8 91.4 345 17.9 92.0 346 7.1 92.1 347172.5 48.8 348 34.3 85.4 349 117.3 67.6 350 15.6 94.3 351 38.9 89.6 352290.0 62.2 353 65.5 49.1 354 19.3 99.5 355 23.3 92.5 356 17.7 84.7 35723.4 72.5 358 21.4 88.8 359 15.3 90.8 360 35.1 75.0 361 127.7 61.3 36226.4 97.0 363 23.8 100.4 364 50.5 79.4 365 35.9 82.7 366 27.4 78.7 36717.6 63.3 368 32.5 82.6 369 73.3 73.8 370 45.3 85.5 371 11.0 94.4 37244.8 78.9 373 38.5 71.4 374 13.4 94.4 375 89.4 55.7 376 45.5 44.2 37725.4 80.9 378 238.3 26.3 379 56.3 72.7 380 35.0 76.0 381 828.2 73.9 38247.1 67.5 383 308.7 66.3 384 6.9 83.8 385 57.1 87.0 386 45.2 66.7 38718.2 81.9 388 4.6 96.2 389 188.5 35.3 390 24.4 95.3 391 11.7 78.3 39217.2 79.1 393 12.0 86.1 394 37.3 94.9 395 20.4 92.4 396 6.4 88.8 39780.9 87.9 398 13.4 91.0 399 7.2 92.1 400 171.9 88.3 401 255.8 74.5 40217.9 77.8 403 9.2 88.6 404 14.3 89.7 405 42.0 95.8 406 10.6 97.5 40973.2 88.7 410 82.1 69.7 413 55.6 47.5 414 504.6 36.4 415 206.2 26.8 416114.8 69.0 423 26.0 73.3 424 67.8 76.7 430 70.4 78.9 431 1593.1 92.7 432163.0 88.4 433 115.4 92.4 434 316.1 96.6 435 305.4 12.3 436 13566.5 58.0437 167.6 16.4 438 34.8 74.6 439 116.6 35.8 440 28291.3 50.1 441 57.064.3 442 302.8 17.2 443 153.4 83.9 444 146.8 46.5 445 9.8 91.3 446 143.784.3 447 335.8 63.1 448 598.6 58.5 449 345.3 30.1 450 307.5 77.6 45113667.2 44.8 452 33.8 84.6 453 13.0 95.9 454 56.2 18.4 BRET β-Arrestin2BRET β-Arrestin2 Example Low AT1R Expression Low AT1R Expression NumberEC₅₀ (nM) Ymax (%) 1 29.5 61.8 2 11.0 15.2 3 24.2 30.6 4 8.2 69.3 5 12.122.9 8 5.4 80.5 9 9.4 80.3 10 2.4 86.8 11 35.3 16.9 14 >10000 19 12.173.7 20 12.2 59.5 24 13.9 21.6 25 32.9 10.1 29 18.9 42.2 30 14.5 72.9 3184.7 42.4 32 12.5 80.9 33 26.7 27.5 53 14.0 61.8 56 54.0 14.2 57 19.98.9 59 >10000 60 93.3 39.4 61 108.3 38.2 62 3.7 74.7 63 26.5 59.3 64 3.198.7 65 23.6 54.5 66 16.6 39.4 67 14.5 40.7 68 15.3 91.1 72 58.2 44.4 7837.5 85.0 79 464.4 21.1 80 30.4 29.8 81 38.3 16.3 83 152.1 43.191 >10000 92 309.2 66.5 110 95.5 22.1 111 14.7 80.7 112 174.3 39.3 1139.8 88.6 114 36.6 57.2 115 16.8 53.3 116 17.2 81.9 117 >100000 118 172.678.7 119 53.9 63.9 120 34.3 50.1 122 30.8 31.6 127 17.3 29.5 129 >10000133 >10000 138 >10000 139 41.4 83.5 141 40.4 58.9 146 52.6 35.0 147109.2 26.1 148 140.7 17.7 149 82.7 42.1 150 76.9 65.7 151 419.2 42.5 15221.8 47.9 153 54.1 34.1 154 63.9 82.9 155 42.7 31.4 156 250.1 22.1 15761.1 86.5 159 40.3 64.9 160 98.5 74.5 161 46.3 54.4 162 372.7 41.9 16391.8 45.7 164 159.6 85.0 165 281.3 69.1 166 64.5 81.0 167 58.3 97.4 168997.9 26.5 169 270.9 59.9 170 590.4 65.3 171 68.4 67.5 172 >10000 17380.4 81.8 174 634.1 25.0 175 10.7 73.1 176 30.6 17.8 177 11.5 84.1 17819.4 80.7 179 61.4 55.4 180 178.3 66.3 181 15.7 89.4 182 26.3 73.5 183137.9 54.6 186 22.8 80.0 187 180.9 45.4 188 24.6 82.4 189 49.2 77.2 190154.1 72.1 191 76.0 75.5 192 127.2 22.6 193 132.9 92.2 194 294.8 53.2195 281.9 73.0 196 1700.3 45.2 197 >10000 204 9.8 37.1 205 21.3 72.2 20826.4 67.5 209 50.0 80.0 210 28.4 49.5 214 15.9 100.6 215 4.1 77.5 2166.6 67.3 217 3.0 102.6 218 >10000 219 33.2 33.6 220 36.0 63.8 221 158.732.4 222 98.5 33.8 223 9.2 54.5 224 7.6 60.6 225 187.0 51.8 227 31.486.1 228 209.9 66.6 230 140.2 10.1 231 98.8 85.7 232 101.4 34.1 233 9.7107.9 234 12.2 96.5 235 128.6 67.0 236 17.3 107.0 237 111.8 71.7 239 9.0112.7 240 344.8 62.0 241 50.2 60.8 242 28.2 92.5 243 71.5 58.2 244 111.055.8 245 24.1 83.8 246 916.2 52.2 247 22.7 17.7 250 11.0 49.2 251 8.219.0 253 46.0 42.3 254 59.1 37.6 255 87.8 36.3 256 34.5 77.4 257 29.144.2 258 81.9 27.3 259 38.8 71.7 260 49.9 53.5 262 14.3 71.5 264 12.987.4 265 18.9 98.5 266 5.7 105.1 267 8.2 102.1 295 39.0 46.3 299 4.7104.3 300 12.8 70.3 301 14.8 87.0 302 14.9 84.2 303 38.2 81.7 304 38.381.2 305 90.3 91.5 306 133.5 99.3 307 962.0 27.1 309 6.5 109.1 310 10.9109.0 311 4.2 80.0 312 5.8 71.0 313 21.5 62.6 314 36.6 78.7 322 9.7 31.7323 24.4 41.2 324 63.2 71.8 325 201.3 59.5 326 24.7 42.4 327 33.0 39.7330 16.7 44.6 331 8.4 45.3 332 12.1 18.9 333 11.3 33.9 334 5.9 73.1 3356.0 21.1 336 12.4 37.6 337 631.1 96.2 338 16.3 81.2 339 12.8 40.4 3405.8 64.3 341 12.2 54.7 342 3.6 78.7 343 26.2 47.0 344 767.3 52.1 34611.1 49.8 384 10.8 29.2 388 26.7 98.4 390 97.0 53.7 391 11.0 29.6 39614.1 52.9 404 69.4 54.7 410 98.2 23.0 418 154.2 27.1 419 85.2 21.5 42435.3 19.7 425 47.4 35.0 426 49.6 40.7 427 >10000 6.5 428 121.9 12.1 44536.0 92.0 455 181.7 13.2 456 1965.2 26.7 457 993.4 35.1 458 385.3 52.4459 1241.1 18.9 Example IP-1 IP-1 Number EC₅₀ (nM) Ymax (%) 1 20.7 18.72 71.8 13.1 3 45603.6 29.9 4 19.0 9.8 5 23.8 15.1 6 14.6 4.9 7 83.9 9.28 6.0 6.9 9 8.7 7.1 10 5.0 14.4 11 17.8 3.8 12 >1000 13 >1000 14 14.58.1 15 21.7 2.4 16 55.3 3.6 17 8.7 3.3 18 499.1 15.4 19 27.4 12.2 2012.8 9.9 21 77.3 6.9 22 34.4 2.4 23 211.0 7.3 24 20.7 14.5 25 40.8 6.726 24.2 7.5 27 >100000 28 3779.3 2.3 29 38.7 12.1 30 15.9 12.3 31 233.812.3 32 38.4 10.8 33 80.8 3.3 34 177.8 3.8 35 >50000 39 126.1 4.8 4011.9 8.5 45 14.4 14.5 46 354.8 15.4 47 6.2 3.8 48 356.7 10.0 49 21.0 4.250 132.1 6.7 51 92.1 3.7 52 >1000 53 7.9 5.8 54 10.5 7.0 55 26.8 6.856 >100000 57 >100000 58 426.5 3.1 59 21.9 10.4 60 83.1 5.3 61 150.3 9.862 29.0 22.7 63 51.3 21.4 64 23.2 30.8 65 62.7 12.2 66 8.5 6.9 67 26.510.2 69 >100000 70 >50000 71 48592.6 11.8 72 92.0 8.5 73 5940.0 11.674 >100000 75 >100000 76 >100000 77 203.6 7.1 78 79.5 37.8 79 498.6 9.480 425.2 14.6 81 >100000 82 >100000 83 26.9 9.0 84 126.1 6.6 85 >10000086 >100000 87 42.0 7.2 88 >100000 89 >100000 90 39.8 6.0 91 >100000 921395.2 51.1 93 21.2 5.4 94 32.7 9.0 95 248.9 6.3 96 28.7 5.3 97 47.3 7.398 26.7 6.6 99 >100000 100 49.9 6.1 101 >100000 102 723.5 3.8103 >100000 104 >100000 105 >100000 106 >100000 107 >100000 108 219.512.8 109 >100000 110 108.3 9.0 111 12.6 15.7 112 284.4 7.7 113 83.5 17.8114 121.9 8.3 115 39.3 13.6 116 39.7 15.1 117 >100000 118 154.8 17.1 119108.3 18.4 120 75.3 20.7 121 367.7 7.2 122 35.4 5.5 123 >100000124 >100000 125 >100000 126 >100000 128 >100000 129 119.1 2.0 130 108.35.9 131 >100000 133 >100000 134 101.6 4.0 135 >100000 136 14.4 18.1137 >100000 138 54.1 6.3 139 19.2 16.8 140 26.1 4.5 141 >100000 142140.1 4.8 143 18.3 5.2 144 >100000 145 57.1 3.1 146 76.2 8.3 147 177.53.6 148 310.7 6.1 149 142.7 7.5 150 20.7 17.2 151 606.5 14.0 152 30.77.0 153 228.9 6.0 154 40.6 14.4 155 >100000 156 189.0 7.2 157 60.1 11.4158 214.4 8.6 159 78.1 11.3 160 132.1 15.8 161 203.3 14.2 162 234.6 8.9163 180.7 7.8 164 231.4 17.3 165 191.9 17.7 166 103.3 14.8 167 165.232.4 168 825.5 13.8 169 484.0 14.5 170 468.7 13.2 171 8124.9 68.1 172782.4 9.4 175 12.8 24.1 176 48.9 9.8 177 112.5 22.9 178 21.5 20.8 17981.7 12.2 180 226.5 27.5 181 78.4 6.1 182 131.7 6.6 183 200.3 14.1 184109.6 12.0 185 203.6 13.8 186 85.9 22.2 187 103.7 16.1 188 172.8 24.2189 18.4 12.7 190 485.2 17.5 191 118.2 29.9 192 223.3 11.1 193 132.425.0 194 213.7 14.5 195 357.9 5.3 196 868.9 12.1 197 492.6 5.7 198 645.914.6 199 713.4 9.3 200 2718.8 11.4 201 453.9 5.6 202 2935.9 5.7 2035366.6 34.9 204 66.8 14.4 205 70.2 16.7 206 35.4 4.8 207 39.1 2.5 208105.8 19.9 209 110.3 25.5 210 82.7 14.8 211 234.9 8.7 212 20.1 3.8 213861.6 6.9 214 89.6 50.0 215 17.6 17.3 216 29.1 10.6 217 22.5 21.8 21833.3 4.6 219 117.5 6.9 222 187.3 4.9 225 25.2 7.0 226 499.4 6.7 227268.5 9.8 228 146.7 13.0 229 195.5 6.7 230 340.4 12.7 231 30.1 8.4 23260.0 7.5 233 31.3 10.2 234 19.3 18.8 235 213.1 14.9 236 48.2 19.2 23779.7 13.7 238 1255.5 9.6 239 30.7 34.2 240 122.4 14.1 241 150.3 12.8 24352.0 14.7 244 200.7 11.0 245 89.4 12.7 246 281.4 4.8 247 >100000 24881.7 6.8 249 70.5 17.6 250 50.5 28.9 251 182.5 10.9 252 144.2 8.8 253133.2 18.7 254 176.5 30.0 255 471.1 7.8 257 28.3 10.7 258 42.8 15.1 25921.1 9.9 260 174.7 18.5 261 781.8 11.5 262 37.9 8.6 264 42.8 15.1 26529.2 15.6 266 26.1 17.7 267 36.6 10.9 268 1093.8 7.0 269 >100000 2704681.8 6.7 271 589.7 2.9 272 >100000 273 154.6 3.3 274 1491.5 3.5275 >100000 276 400.8 3.5 277 >100000 278 1208.5 2.1 279 >100000 2802865.4 3.8 281 231.7 3.2 283 155.0 4.2 284 151.2 7.5 285 1535.4 7.9 286301.7 5.3 287 >100000 288 >100000 289 546.5 4.3 290 502.5 4.7291 >100000 292 >100000 293 1240.6 8.5 294 427.2 5.4 295 216.9 7.2 296619.2 11.0 297 620.5 6.6 298 957.7 5.8 299 21.3 20.3 302 47.3 16.9 303108.7 20.1 305 82.9 10.1 308 27.3 22.3 309 7.9 17.2 310 35.3 21.3 31118.1 10.6 312 20.7 8.9 313 82.1 6.1 314 128.9 5.6 315 >100000316 >100000 317 17118.1 9.9 318 552.2 8.4 319 786.6 7.9 320 >100000 32147.9 9.9 322 93.3 5.9 323 >100000 324 42.3 7.9 326 16.2 5.3 327 22.112.6 328 2622.6 7.9 329 31.5 9.4 330 40.1 8.1 331 26.4 8.5 332 105.7 4.9333 17.8 6.2 334 41.3 10.7 335 721.3 3.9 336 47.2 8.7 337 55.8 7.1 33830.8 6.2 339 52.1 5.7 345 12.5 7.4 346 67.1 6.4 347 242.2 5.7 348 89.25.2 349 173.7 3.5 350 25.3 4.5 351 81.1 4.6 352 1178.2 6.8 353 565.6 5.9354 45.5 3.4 355 >1000 356 36.7 3.3 357 46.3 3.3 358 44.7 4.3 359 39.46.4 360 >100000 361 295.5 5.1 362 34.2 3.1 363 59.6 6.5 364 118.8 5.3365 40.8 4.2 366 42.9 3.5 367 59.1 3.9 368 96.1 2.1 369 172.9 4.4 37071.9 9.3 371 >1000 372 73.8 5.5 373 734.5 5.4 374 16.2 7.7 375 272.9 8.7376 123.0 5.0 377 145.9 4.2 378 688.5 7.5 379 106.3 5.4 380 103.8 6.3381 2109.2 5.3 382 >100000 383 7742.2 11.0 384 39.1 4.2 385 1109.5 10.3386 59063.4 21.2 387 3416.2 13.6 388 810.2 23.4 389 2022.2 6.3 390 23.710.1 391 181.0 4.5 392 3322.3 6.7 393 48.8 5.7 394 76.4 3.1 395 12.7 6.0396 273.6 3.1 397 124.0 5.3 398 35.1 13.0 399 1166.8 10.1 400 891.6 4.5401 2238.4 5.0 402 64.9 2.3 403 70.9 4.1 404 70.4 3.7 405 491.7 3.3 40716587.0 43.4 408 >100000 409 135.5 8.0 410 >100000 411 17.0 4.8 412 62.76.0 413 350.8 5.4 414 460.1 5.2 415 486.7 3.6 416 >100000 417 >100000418 478.5 5.3 419 227.8 4.4 420 79.7 8.2 421 92.5 5.5 422 209.5 7.1 42325.4 3.5 424 2788.6 7.0 425 104.7 8.3 426 86.0 5.6 427 574.9 5.4 430275.2 2.1 431 910.5 3.2 432 285.5 3.9 433 581.1 5.2 434 1278.6 8.2435 >100000 436 >100000 437 >100000 438 718.0 4.9 439 386.2 3.9 440582.3 2.7 441 >100000 442 >100000 443 77.1 8.6 444 258.3 6.2 445 140.413.2 446 >100000 447 1384.5 9.0 448 856.2 4.4 449 >100000 450 5264.011.1 451 4107.7 6.2 452 44.8 4.4 453 24.0 4.2 454 >100000 455 93.8 4.0Example BRET P63 BRET P63 Number EC₅₀ (nM) Ymax (%) 2 22.0 2.7 4 4.813.0 8 7.7 14.0 9 19.5 14.2 10 2.8 26.1 14 >10000 20 10.8 12.025 >100000 30 19.1 23.5 32 21.1 25.2 33 >10000 53 >100000 56 42.6 4.0 5714.3 5.0 59 >10000 60 >10000 61 22.3 6.4 62 4.2 35.7 63 23.2 12.4 64 2.641.3 65 17.2 13.1 66 >10000 67 7.3 14.3 68 15.0 41.7 72 43.0 11.8 7872.3 36.1 79 >10000 80 >100000 81 >100000 83 54.8 8.2 91 >100000 92278.0 17.8 110 >100000 111 22.3 24.1 112 46.8 8.2 113 17.2 28.6 114 66.511.8 115 11.9 22.1 116 14.7 27.7 117 >100000 118 101.9 21.8 119 40.521.8 120 18.4 17.8 122 >10000 127 >10000 133 >10000 139 34.4 20.6 14113.3 14.9 146 >100000 147 >100000 150 105.1 14.6 151 174.2 11.0152 >100000 153 >100000 154 57.7 25.3 155 >100000 156 >100000 157 37.616.5 159 79.3 11.5 160 79.7 18.6 161 49.6 10.9 162 >10000 163 >10000 164105.9 15.6 165 261.6 14.1 166 65.0 22.7 167 91.5 32.0 168 >10000 169127.1 13.3 170 632.7 13.5 171 30.9 20.1 172 >10000 173 79.1 19.3 174770.1 10.3 175 21.1 12.4 176 >100000 177 36.2 23.8 178 25.6 19.6 17952.3 11.6 180 209.8 14.9 181 47.5 16.1 183 179.4 13.2 185 446.7 11.7 18633.0 14.7 187 167.7 8.4 188 33.1 17.2 189 32.1 17.5 190 432.4 16.4 191100.9 24.2 192 >100000 193 160.4 29.3 194 278.2 16.2 195 264.0 13.6 1961098.0 7.6 197 >100000 198 7623.5 13.4 199 570.7 9.6 200 2041.1 4.3202 >100000 203 154.0 5.4 204 10.7 9.4 205 18.4 20.2 208 13.3 17.4 20937.6 32.6 214 35.6 43.3 215 4.0 22.7 216 1.8 10.1 217 2.7 32.1218 >10000 220 36.8 18.2 221 28.0 5.4 222 >100000 223 5.9 9.8 224 11.320.8 225 29.5 7.1 226 >100000 227 30.4 19.9 228 125.0 11.4 229 >100000230 >100000 231 36.2 13.8 232 >100000 233 13.2 17.9 234 28.2 37.1 235160.9 17.7 236 34.6 36.2 237 60.5 21.1 238 >100000 239 16.7 44.3 24060.1 9.5 241 40.5 17.5 242 41.6 45.6 243 42.1 15.2 244 69.6 15.3 24527.2 23.3 246 82.6 10.1 247 >10000 249 9.5 6.6 250 9.3 14.1 251 11.1 6.7252 >100000 253 38.3 12.6 254 39.9 7.1 255 22.5 6.0 256 43.0 30.5 25723.7 10.8 258 139.6 17.5 260 >100000 261 >100000 262 11.2 14.4 264 7.415.7 265 7.0 17.9 266 5.7 19.1 267 7.5 17.7 293 >100000 294 >100000 295119.7 12.9 296 306.6 6.9 297 >100000 298 >100000 299 4.9 31.7 300 9.025.1 301 13.6 31.2 302 10.2 25.2 303 49.7 30.4 304 29.7 17.3 305 67.024.3 306 104.3 24.8 307 >10000 309 3.8 28.6 310 7.2 29.1 311 3.6 13.2312 17.2 9.4 313 46.7 6.3 314 67.8 12.8 322 53.7 5.1 323 >10000324 >10000 325 >10000 326 >100000 327 26.9 10.8 330 >10000 331 >10000332 >10000 333 >10000 334 15.7 13.9 335 >10000 336 >10000 337 >10000338 >10000 339 >10000 340 2.9 17.3 341 4.4 18.8 342 3.3 16.5 343 26.715.3 344 16.8 10.4 346 19.3 6.0 384 >10000 388 39.8 30.4 390 127.1 11.9391 >100000 392 >100000 396 >100000 404 >10000 410 >10000 418 >10000419 >10000 424 >100000 425 >10000 426 >10000 427 >10000 428 >10000 443364.6 4.5 444 >100000 445 102.6 24.0 446 668.0 4.5 447 >100000448 >100000 449 >100000 450 >100000 455 >100000 456 1867.0 9.4 4571139.9 31.5 458 253.0 31.7 459 >10000

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-humanorganism that could potentially benefit from treatment with an AIIbiased agonist, or β-Arrestin agonist of the angiotensin II receptor.Exemplary subjects include human beings of any age with risk factors fordevelopment of heart failure and the sequelae thereof, angina, ischemia,cardiac ischemia, myocardial infarction, reperfusion injury,angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia, stroke, as well as atherosclerosis,coronary artery disease, acute coronary syndrome, and/or dyslipidemias.

As used herein, “treating” or “treatment” cover a treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting a disease-state, i.e., arresting it development; and/or (b)relieving a disease-state, i.e., causing regression of a disease state.

As used herein, “prophylaxis” is the protective treatment of a diseasestate to reduce and/or minimize the risk and/or reduction in the risk ofrecurrence of a disease state by administering to a patient atherapeutically effective amount of at least one of the compounds of thepresent invention or a or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Patients may be selected forprophylaxis therapy based on factors that are known to increase risk ofsuffering a clinical disease state compared to the general population.For prophylaxis treatment, conditions of the clinical disease state mayor may not be presented yet. “Prophylaxis” treatment can be divided into(a) primary prophylaxis and (b) secondary prophylaxis. Primaryprophylaxis is defined as treatment to reduce or minimize the risk of adisease state in a patient that has not yet presented with a clinicaldisease state, whereas secondary prophylaxis is defined as minimizing orreducing the risk of a recurrence or second occurrence of the same orsimilar clinical disease state.

As used herein, “prevention” cover the preventive treatment of asubclinical disease-state in a mammal, particularly in a human, aimed atreducing the probability of the occurrence of a clinical disease-state.Patients are selected for preventative therapy based on factors that areknown to increase risk of suffering a clinical disease state compared tothe general population.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to modulate AII biased agonism, or β-Arrestinagonism of the angiotensin II receptor to prevent or treat the disorderslisted herein. When applied to a combination, the term refers tocombined amounts of the active ingredients that result in the preventiveor therapeutic effect, whether administered in combination, serially, orsimultaneously.

In addition to their affects due to their activity as biased agonists orβ-Arrestin agonists of the Angiotensin II Receptor, due to theirAngiotensin II receptor activity, the compounds of the invention may beused in the treatment, prevention and/or prophylaxis of multiplediseases or disorders associated with the AT1R, such as heart failuresuch as acute decompensated heart failure (ADHF), chronic heart failure,fibrosis atrial fibrillation, coronary artery disease, peripheralvascular disease, atherosclerosis, renal disease, diabetes, obesity,metabolic syndrome, hypertension, pulmonary hypertension,cerebrovascular disorders and the sequelae thereof, cardiovasculardisorders, angina, ischemia, stroke, myocardial infarction, acutecoronary syndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes and obesity.

In addition to their affects due to their activity as biased agonists orβ-Arrestin agonists of the Angiotensin II Receptor, due to theirAngiotensin II receptor activity, the compounds of the invention may beused in the treatment, prevention and/or prophylaxis of multiplediseases or disorders associated with the AT1R, such as of heartfailure, coronary artery disease, peripheral vascular disease,atherosclerosis, fibrosis, diabetes, obesity, metabolic syndrome,insulin resistance, hypertension, pulmonary hypertension, atrialfibrillation, angina, ischemia, stroke, myocardial infarction, acutecoronary syndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes, obesity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

Additionally, the compounds may be useful for the treatment and/orprophylaxis of heart failure, coronary artery disease, cardiomyopathy,atrial fibrillation, and related conditions including but not limited toacute coronary syndrome, myocardial ischemia, hypertension,atherosclerosis, pulmonary hypertension, peripheral arterial disease,ischemia/reperfusion injury, angina, renal disease,

V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND COMBINATIONS

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; bucally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.

Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, Jr., L. V. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012),

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more other therapeutic agent(s), e.g., agents used intreatment of heart failure or other pharmaceutically active material.

The compounds of the present invention may be employed in combinationwith one or more other suitable therapeutic agents useful in thetreatment of the aforementioned disorders including: agents for treatingheart failure, anti-hypertensive agents, anti-atherosclerotic agents,anti-dyslipidemic agents, anti-diabetic agents, anti-hyperglycemicagents, anti-hyperinsulinemic agents, anti-thrombotic agents,anti-retinopathic agents, anti-neuropathic agents, anti-nephropathicagents, anti-ischemic agents, anti-obesity agents, anti-hyperlipidemicagents, anti-hypertriglyceridemic agents, anti-hypercholesterolemicagents, anti-restenotic agents, anti-pancreatic agents, lipid loweringagents, anorectic agents, memory enhancing agents, anti-dementia agents,cognition promoting agents, appetite suppressants, and agents fortreating peripheral arterial disease.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents in treatingheart failure and coronary artery disease: ACE inhibitors (such asenalapril), neprilysin inhibitors (such as sacubitril), β-blockers,diuretics (such as furosemide), mineralocorticoid receptor antagonists,renin inhibitors, calcium channel blockers, nitrates, digitaliscompounds, inotropic agents and β-receptor agonists, anti-hyperlipidemicagents, plasma HDL-raising agents, anti-hypercholesterolemic agents,cholesterol biosynthesis inhibitors (such as HMG CoA reductaseinhibitors), LXR agonist, probucol, raloxifene, nicotinic acid,niacinamide, cholesterol absorption inhibitors, bile acid sequestrants(such as anion exchange resins, or quaternary amines (e.g.,cholestyramine or colestipol), low density lipoprotein receptorinducers, clofibrate, fenofibrate, benzofibrate, cipofibrate,gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidant vitamins,anti-diabetes agents, platelet aggregation inhibitors, fibrinogenreceptor antagonists, aspirin and fibric acid derivatives.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-diabetic agentsdepending on the desired target therapy. Studies indicate that diabetesand hyperlipidemia modulation can be further improved by the addition ofa second agent to the therapeutic regimen. Examples of anti-diabeticagents include, but are not limited to, sulfonylureas (such aschlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide,gliclazide, glynase, glimepiride, and glipizide), biguanides (such asmetformin), thiazolidinediones (such as ciglitazone, pioglitazone,troglitazone, and rosiglitazone), and related insulin sensitizers, suchas selective and non-selective activators of PPARα, PPARβ and PPARγ;dehydroepiandrosterone (also referred to as DHEA or its conjugatedsulphate ester, DHEA-SO₄); anti-glucocorticoids; TNFα inhibitors;dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin,saxagliptin), GLP-1 agonists or analogs (such as exenatide),α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose),pramlintide (a synthetic analog of the human hormone amylin), otherinsulin secretagogues (such as repaglinide, gliquidone, andnateglinide), insulin, as well as the therapeutic agents discussed abovefor treating heart failure and atherosclerosis.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-obesity agentsselected from phenylpropanolamine, phentermine, diethylpropion,mazindol, fenfluramine, dexfenfluramine, phentiramine, β₃-adrenergicreceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors(such as orlistat), and leptins. Other agents used in treating obesityor obesity-related disorders include neuropeptide Y, enterostatin,cholecytokinin, bombesin, amylin, histamine H₃ receptors, dopamine D₂receptor modulators, melanocyte stimulating hormone, corticotrophinreleasing factor, galanin and gamma amino butyric acid (GABA).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients but also to control the release of one of these componentsin the gastrointestinal tract such that one of these components is notreleased in the stomach but rather is released in the intestines. One ofthe active ingredients may also be coated with a material that affects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the AT1R and AII, orbiased agonists orβ-Arrestin agonists of the angiotensin II receptor. Such compounds maybe provided in a commercial kit, for example, for use in pharmaceuticalresearch involving AT1R and AII, or biased agonists or β-Arrestinagonists of the angiotensin II receptor, or anti-heart failure activity.For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimenter that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving AT1R and AII, or biased agonists or β-Arrestin agonismof the angiotensin II receptor.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises a first therapeutic agent, comprising a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment and/or prophylaxis of multiple diseases ordisorders associated with AT1R and AII, or biased agonism or β-Arrestinagonism of the angiotensin II receptor, (as defined previously). Inanother embodiment, the package insert states that the pharmaceuticalcomposition can be used in combination (as defined previously) with asecond therapeutic agent for the treatment and/or prophylaxis ofmultiple diseases or disorders associated with AT1R and AII, or biasedagonism or β-Arrestin agonism of the angiotensin II receptor. Thearticle of manufacture can further comprise: (d) a second container,wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

1.-12. (canceled)
 13. A compound of formula (I), or salt thereof:

wherein ring A is

W is N, or CR¹⁶, W′, at each occurrence, is independently selected fromN, O, S and CR¹⁶ where at least one W′ is not CR¹⁶, and at most only oneW′ is selected as O or S; R¹ and R² are independently selected from H,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxyalkyl, andC₃-C₆ cycloalkyl; alternatively, R¹ and R², together with the atom towhich they are attached, join together to form a C₃-C₆ cycloalkyl, or a4 to 6 membered heterocycle having 1-2 heteroatoms, the cycloalkyl orheterocycle is substituted with 0-4 F and 0-1 OH; R¹⁶, at eachoccurrence, is independently selected from H, F, Cl, Br, I, CN, OH,N(R^(a))₂, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₁-C₄-hydroxyalkyl, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkyl, andC₃-C₆-halocycloalkyl R^(a) is, at each occurrence, independentlyselected from H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-hydroxyalkyl, andC₃-C₆-cycloalkyl; or two R^(a), along with the nitrogen atom to whichthey are attached, join to form a 5 to 6 membered heterocycle containing0-2 additional heteroatoms selected from N, O and S; Y is 5-tetrazolyl,SO₃H, PO₂H₂, PO₃H₂, COOR,

R, at each occurrence, is independently selected from H, C₁-C₆ alkyl,C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl, C₆₋₁₀-aryl-C₁-C₆alkyl, heterocycle-C₁-C₆ alkyl, wherein said heterocycle is a 4-10membered group having 1-3 heteroatoms selected from N, O, or S, saidaryl and heterocycle are each substituted with 0-3 groups chosen fromC₁-C₃ alkyl, halo, OH, or C₁-C₃ fluoroalkyl; R^(s) at each occurrence,is independently selected from H, C₁-C₆ alkyl, C₁-C₆-haloalkyl,C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-C₁-C₃ alkyl,C₆₋₁₀ aryl, C₆₋₁₀-aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,heterocyclyl, heterocycle-C₁-C₆-alkyl, wherein the heteroaryl andheterocycle are each a 4-10 membered group having 1-3 heteroatomsselected from N, O, or S; Z, at each occurrence, is independentlyselected from a bond, O, S, N(R^(z)), C(R^(z))₂, C═O, C(═O)N(R^(z)),N(R^(z))C(═O), C(R^(z))₂C(R^(z))₂, OC(R^(z))₂, SC(R^(z))₂,N(R^(z))C(R^(z))₂, C(R^(z))₂O, C(R^(z))₂S, C(R^(z))₂N(R^(z)); R^(z) isat each occurrence independently selected from H, C₁-C₄-alkyl,C₁-C₄-hydroxyalkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl or, alternatively,two R^(z) groups either on the same atom or on adjacent atoms can jointo form a C₃-C₆-cycloalkyl or a 4 to 7 membered heterocycle containing1-2 heteroatoms selected from N, O and S; G is selected from a 4 to 11membered heterocycle having 1-4 atoms selected from N, O, and S, aC₃-C₈-cycloalkyl, C₆-C₁₀-aryl or a 5 to 10 membered heteroaryl having1-4 atoms selected from N, O, and S; wherein the heterocycle,cycloalkyl, aryl and heteroaryl are substituted with 0-3 substituentsindependently selected from the group consisting of ═O, F, Cl, Br, I,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, OH,OR^(x), SR^(x), N(R^(x))₂, CO(R^(x)), CON(R^(x))₂, CO₂R^(x),N(R^(x))CO₂(R^(x)), N(R^(x))CO(R^(x)), N(R^(x))CON(R^(x))₂,S(O)₂(R^(x)), S(O)₂N(R^(x))₂, or N(R^(x))S(O)₂(R^(x)); R^(x) is H, C₁₋₆alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, phenyl, CH₂-phenyl; ring B is

Group C is

R⁵ is C₁₋₆ alkyl, C₁₋₆ haloalkyl C₁₋₆ alkoxyalkyl,C₃₋₆-cycloalkylC₀₋₄-alkyl which may be substituted with 1-3 halogens ora C₁₋₃-alkoxy group; R⁶ is H, F, Cl, Br, CF₃, CN, N(R^(z))₂,CON(R^(z))₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl C₁₋₄ alkoxyalkyl, C₁₋₄hydroxyalkyl, C₃₋₆-cycloalkyl, C₃₋₆-halocycloalkyl,C₃₋₆-alkoxycycloalkyl, or C₃₋₆-hydroxycycloalkyl; R⁹ is COOR,CON(R^(z))₂; and r is 0 to 3; provided that the compounds of Formula (I)are not


14. A compound of claim 13, or salt thereof, wherein R⁵ is C₁₋₆ alkyl,C₃₋₆ cycloalkyl or O(C₁₋₆ alkyl); R⁹ is CO₂H, CO₂-C₁₋₆-alkyl, CO₂NH₂,CO₂NH(C₁₋₆-alkyl), CO₂N(C₁₋₆-alkyl)₂. and R⁶ is hydrogen, or C₁₋₄ alkyl.15. A compound of claim 13, or salt thereof, wherein G is selected froma 5 to 10 membered heterocycle having 1-3 atoms selected from N, O, andS, phenyl or a C₆-C₁₀-heteroaryl having 1-3 atoms selected from N, O,and S; wherein the heterocycle, phenyl and heteroaryl are substitutedwith 0-3 substituents independently selected from the group consistingof ═O, Cl, Br, I, F, C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl,C₁-C₆-alkylthio, C₁-C₆-hydroxyalkyl, OH, OR^(x), N(R^(x))₂, CO(R^(x)),CON(R^(x))₂, CO₂R^(x), N(R^(x))CO₂(R^(x)), N(R^(x))CO(R^(x)),N(R^(x))CON(R^(x))₂, S(O)₂(R^(x)), S(O)₂N(R^(x))₂, orN(R^(x))S(O)₂R^(x); R^(x) is H, C₁₋₆ alkyl, CF₃, phenyl, CH₂phenyl. 16.A compound of claim 13, or salt thereof, wherein Ring B is

any of which are optionally substituted with 0-2 F,
 17. A compound ofclaim 13, or salt thereof, wherein Ring B is

any of which are optionally substituted with 0-2 F, Y is COOH, COOMe,COOEt,

5-tetrazolyl, SO₃H,


18. A compound of claim 13, or salt thereof, wherein wherein Y is COOH,5-tetrazolyl, SO₃H,

and R═C₁₋₆ alkyl, C₆₋₁₀-aryl-C₁-C₆-alkyl, or (CH₂Ph).
 19. A compound ofclaim 13, or salt thereof, wherein Ring A is

and R^(a) is H or F.
 20. A compound of claim 13, or salt thereof,wherein G is selected from a phenyl, thiophenyl, quinolinyl,isoquinolinyl, indolyl, pyrazolyl, pyrrolyl, pyridinyl, isoindolinyl,pyrrolidinyl; any of which are substituted with 0-3 substituentsindependently selected from the group consisting of ═O, Cl, Br, I, F,C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, OH, OR^(x), N(R^(x))₂,CO(R^(x)), CON(R^(x))₂, CO₂R^(x), N(R^(x))CO₂(R^(x)), N(R^(x))CO(R^(x)),N(R^(x))CON(R^(x))₂, S(O)₂(R^(x)), S(O)₂N(R^(x))₂, orN(R^(x))S(O)₂R^(x); R^(x) is H, C₁₋₃ alkyl, CF₃, phenyl, CH₂phenyl. 21.A compound of claim 13, or salt thereof, wherein Y is carboxyl,5-tetrazolyl,

and R is C₁₋₆ alkyl.
 22. A compound of claim 13, or salt thereof,wherein Ring B is

any of which are substituted with 0-2 F.
 23. A compound of claim 13, orsalt thereof wherein Ring B is

Ring A is

Z is a bond or NR^(a); G is isoindolinyl-1,3-dione,pyrrolidine-2,5-dione, phenyl, thiazolyl, pyridinyl, pyrrolyl,pyrazolyl, quinolinyl, isoquinolinyl, any of which may be substitutedwith 0-3 substituents selected from ═O, C₁₋₄ alkyl, —O—R^(x), C₁₋₄haloalkyl, —C(O)NR^(x), —N(R^(x))₂, and F; R⁵ is C₃₋₄ alkyl; R⁶ is C₃₋₄alkyl; R^(a) is hydrogen, C₁₋₄alkyl, and C₁₋₂haloalkyl; and Y istetrazolyl, COOH, 1,2,4-oxadiazol-5(4H)-one, or —SO₂NHCOO-nbutyl.24.-25. (canceled)
 26. A method for the treatment or prophylaxis ofdiseases or disorders which can be modulated by biased agonism orβ-Arrestin agonism of the angiotensin II receptor, comprisingadministering to a patient in need of such treatment or prophylaxis atherapeutically effective amount of at least one of the compounds ofclaim 13, wherein the disease or disorder is preserved injectionfraction heart failure, reduced injection heart failure, and/or renaldisease.
 27. A method for the treatment or prophylaxis of diseases ordisorders which can be modulated by biased agonism or β-Arrestin agonismof the angiotensin II receptor of claim 23, wherein the compound isadministered in combination with at least one other type of therapeuticagent.
 28. A method for the treatment or prophylaxis of diseases ordisorders, comprising administering to a patient in need of suchtreatment or prophylaxis a therapeutically effective amount of at leastone of the compounds of claim 13, wherein the disease or disorder ispreserved injection fraction heart failure, reduced injection heartfailure, and/or renal disease.
 29. A method for the treatment orprophylaxis of diseases or of claim 27, wherein the compound isadministered in combination with at least one other type of therapeuticagent.
 30. A compound of formula (X), or salt thereof:

or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, wherein: ring Ais

W is N, or CR¹⁶; W′, at each occurrence, is independently selected fromN, O, S and CR¹⁶, wherein at least one W′ is not CR¹⁶, and at most onlyone W′ is selected as O or S; R¹ and R² are independently selected fromH, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxyalkyl,and C₃-C₆ cycloalkyl; alternatively, R¹ and R², together with the atomto which they are attached, join together to form a C₃-C₆ cycloalkyl, ora 4 to 6 membered heterocycle having 1-2 heteroatoms, the cycloalkyl orheterocycle is substituted with 0-4 F and 0-1 OH; R¹⁶, at eachoccurrence, is independently selected from H, F, Cl, Br, I, CN, OH,N(R^(a))₂, C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₁-C₄-hydroxyalkyl, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkyl, andC₃-C₆-halocycloalkyl R^(a) is, at each occurrence, independentlyselected from H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-hydroxyalkyl, andC₃-C₆-cycloalkyl; or two R^(a), along with the nitrogen atom to whichthey are attached, join to form a 5 to 6 membered heterocycle containing0-2 additional heteroatoms selected from N, O and S; Y is 5-tetrazolyl,SO₃H, PO₂H, PO₃H₂, COOR,

R, at each occurrence, is independently selected from H, C₁-C₆ alkyl,C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl, C₆₋₁₀-aryl-C₁-C₆alkyl, heterocycle-C₁-C₆ alkyl, wherein said heterocycle is a 4-10membered group having 1-3 heteroatoms selected from N, O, or S, saidaryl and heterocycle are each substituted with 0-3 groups chosen fromC₁-C₃ alkyl, halo, OH, or C₁-C₃ fluoroalkyl; R^(s) at each occurrence,is independently selected from H, C₁-C₆ alkyl, C₁-C₆-haloalkyl,C₁-C₆-hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl C₁-C₃ alkyl,C₆₋₁₀ aryl, C₆₋₁₀-aryl-C₁-C₆-alkyl, heteroaryl, heteroaryl-C₁-C₆-alkyl,heterocyclyl, heterocycle-C₁-C₆-alkyl, wherein the heteroaryl is a 5-10membered group and the heterocycle is a 4-10 membered each having 1-3heteroatoms selected from N, O, or S; Z, at each occurrence, isindependently selected from a bond, O, S, N(R), C(R^(z))₂, C═O,C(═O)N(R^(z)), N(R^(z))C(═O), C(R^(z))₂C(R^(z))₂, OC(R^(z))₂,SC(R^(z))₂, N(R^(z))C(R^(z))₂, C(R^(z))₂O, C(R^(z))₂S,C(R^(z))₂N(R^(z)); R^(z) is at each occurrence independently selectedfrom H, C₁-C₄-alkyl, C₁-C₆-hydroxyalkyl, C₁-C₆-alkoxyalkyl,C₁-C₄-haloalkyl, C₃-C₁₀-cycloalkyl, 5-10-memberedheterocycle-C₁-C₆-alkyl, 5-10-membered heterocycle,C₃-C₁₀-cycloalkyl-C₁-C₆-alkyl, 4 to 7 membered heterocyclyl having 1-2heteroatoms selected from N, O, or S, or, alternatively, two R^(z)groups either on the same atom or on adjacent atoms can join to form aC₃-C₆-cycloalkyl or a 4 to 7 membered heterocycle containing 1-2heteroatoms selected from N, O and S; G is selected from a 4 to 11membered heterocycle having 1-4 atoms selected from N, O, and S, aC₃-C₈-cycloalkyl, C₆-C₁₀-aryl or a 5 to 10 membered heteroaryl having1-4 atoms selected from N, O, and S; wherein the heterocycle,cycloalkyl, aryl and heteroaryl are substituted with 0-3 substituentsindependently selected from the group consisting of ═O, F, Cl, Br, I,C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-hydroxyalkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkenyl, CH₂-phenyl, OH, OR^(x), SR^(x),N(R^(x))₂, CO(R^(x)), CON(R^(x))₂, CO₂R^(x), N(R^(x))CO₂(R^(x)),N(R^(x))CO(R^(x)), N(R^(x))CON(R^(x))₂, S(O)₂(R^(x)), S(O)₂N(R^(x))₂, orN(R^(x))S(O)₂(R^(x)); R^(x) is H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, phenyl, CH₂-phenyl; ring B is

Group C is

R³ is C₁₋₄ hydroxyalkyl, C₁₋₄ haloalkyl, C₁₋₆-hydroxycycloalkyl,C₁₋₆-halocycloalkyl, COOR, CON(R^(z))₂, 5-6 membered heteroaryl or

R⁴ is H, F, Cl, Br, CF₃, CN, N(R^(z))₂, CON(R^(z))₂, C₁₋₄ alkyl, C₁₋₄haloalkyl C₁₋₄ alkoxyalkyl, C₁₋₄ hydroxyalkyl, C₃₋₆-cycloalkyl,C₃₋₆-halocycloalkyl, C₃₋₆-alkoxycycloalkyl,C₃-C₆-cycloalkyl-C₁-C₆-alkyl, or C₃₋₆-hydroxycycloalkyl; R⁵ is C₁₋₆alkyl, C₁₋₆ haloalkyl; C₁₋₆ alkoxyalkyl, C₃₋₆-cycloalkyl-C₀₋₄-alkylwhich may be substituted with 1-3 halogens or a C₁₋₃-alkoxy group; R⁶ isH, F, Cl, Br, CF₃, CN, N(R^(z))₂, CON(R^(z))₂, C₁₋₄-alkyl,C₁₋₄-haloalkyl, C₁₋₄-alkoxyalkyl, C₁₋₄ hydroxyalkyl, C₃₋₆-cycloalkyl,C₃₋₆-halocycloalkyl, C₁₋₆-alkoxy-C₃-C₆-cycloalkyl, orC₃-6-hydroxycycloalkyl; and R⁷ and R⁸, are independently selected fromH, C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkylor, alternatively, R⁷ and R⁸, along with the atom to which they areattached, can join to form a C₃-C₉ cycloalkyl, a C₃-C₉-halocycloalkyl, aC₃-C₉-hydroxycycloalkyl or a 4 to 7 membered heterocycle having 1-2heteroatoms selected from N, O, or S each of said cycloalkyl andheterocycle being optionally substituted with 1-4 F, OH, C₁₋₄ alkyl,C₁₋₄ haloalkyl C₁₋₄ alkoxyalkyl, or C₁₋₄ hydroxyalkyl, and may be fusedwith a 6-membered aryl or 5-6 membered heteroaryl ring, provided thecompounds of Formula (X) are not